Peptide receptor pharmacology atlas

The peptides on this site are organized by indication category on the navigation, by mechanism on the dossier index, and by clinical-development depth on the decision guides — but the most pharmacologically honest organization is by receptor. Receptor identity determines what a molecule does at the cellular level, who else binds it, what the off-target risks are, and how deep the published characterization of the underlying biology actually runs. Two molecules that share a receptor share the safety frame of that receptor's wider physiology, regardless of how the indication marketing has positioned them. Two molecules that hit different receptors with overlapping clinical indications are not interchangeable in the way the practitioner conversation often treats them.

This atlas walks the major receptor targets of the corpus, one section per receptor or receptor family, with: receptor identity and family classification, tissue distribution, endogenous ligand and signaling cascade, the peptides in this corpus that engage it, and a small set of verified primary references. The depth of pharmacological characterization varies dramatically across the list — from the GLP-1 receptor (decades of multi-trial drug-development literature) to the innate repair receptor (a single elegant mechanism program from two laboratories with stalled clinical development) — and that depth-variance is itself information about how seriously to read the corresponding peptides' efficacy claims.

The atlas is a reference page, not an essay. Each entry is a short structured profile rather than a narrative. Cross-links route the reader to the peptide pages where dosing, safety, and clinical-evidence depth are characterized in detail, and to the existing receptor-class dossiers (the GLP-1 receptor pharmacology dossier, the growth-hormone axis dossier, the mitochondrial peptides dossier, and the healing and angiogenesis dossier) where the receptor pharmacology gets more space than a reference entry can give it.

GHSR-1a — growth hormone secretagogue receptor 1a (the ghrelin receptor)

Family. Class A G-protein-coupled receptor, Gq/PLC pathway with downstream IP3 / DAG / Ca²⁺ mobilization in pituitary somatotrophs; β-arrestin recruitment drives desensitization and internalization with chronic agonism.

Tissue distribution. Anterior-pituitary somatotrophs (the principal GH-release substrate), hypothalamus (arcuate nucleus NPY/AgRP neurons; feeding circuits), cardiomyocytes and vascular endothelium, gastric oxyntic mucosa, pancreatic islets, and several other peripheral tissues. The receptor was originally cloned from human pituitary and hypothalamus by Howard et al., Science 1996, 273:974–977 as an orphan GPCR characterized through expression-cloning against the non-peptidyl secretagogue MK-0677 — three years before its endogenous ligand was identified.

Endogenous ligand. Ghrelin: a 28-amino-acid peptide produced by gastric X/A-like cells, uniquely modified by n-octanoylation of serine 3 by ghrelin O-acyltransferase (GOAT / MBOAT4; identified by Yang et al., Cell 2008, 132:387–396). The acylation is essential for GHSR-1a binding; des-acyl ghrelin circulates at higher concentrations but does not activate the receptor at physiological levels. Ghrelin was isolated and characterized by Kojima et al., Nature 1999, 402:656–660 as the long-sought endogenous ligand for the receptor cloned three years earlier. The orexigenic phenotype was characterized by Tschöp et al., Nature 2000, 407:908–913 — chronic ghrelin administration produces dose-dependent food intake and adiposity gain in rodents, anchoring the broader appetite-stimulation framing the receptor carries today.

Peptides in corpus. Ipamorelin is the selective pentapeptide agonist — clean GH release with no significant elevation of ACTH, cortisol, prolactin, FSH, LH, or TSH at doses 200-fold above the GH-release ED50 in the Raun 1998 characterization. Hexarelin is the earlier-generation hexapeptide GHRP-6 derivative, used clinically through the 1990s but ultimately abandoned commercially in part because its cortisol, prolactin, and ACTH spillover are large and its tachyphylaxis curve is steep. MK-677 / Ibutamoren is a non-peptide spiropiperidine secretagogue — orally bioavailable, ~24-hour functional half-life, producing tonic rather than pulsatile GHSR-1a activation. GHRP-2 and GHRP-6 are the prior-generation peptide agonists on which Ipamorelin and Hexarelin are built; neither is a separate peptide page in this corpus.

Key references. Howard et al. 1996 (receptor cloning); Kojima et al. 1999 (endogenous ligand discovery); Tschöp et al. 2000 (appetite phenotype); Yang et al. 2008 (acylation enzyme). The selective-secretagogue design lineage descends from Bowers et al.'s GHRP-6 paper, Endocrinology 1984, 114:1537–1545, which established that small peptide modifications of met-enkephalin could trigger GH release through a pathway distinct from native GHRH — a finding that anticipated a decade of receptor-identification effort.

GHRH-R — growth hormone-releasing hormone receptor

Family. Class B (secretin family) G-protein-coupled receptor; Gs-coupled with adenylyl cyclase activation and cAMP / PKA signaling in somatotrophs. The receptor is structurally and pharmacologically distinct from GHSR-1a — both converge on GH release but through parallel rather than overlapping pathways, which is the mechanistic rationale underpinning the GHRH-analog + ghrelin-mimetic stacking convention.

Tissue distribution. Anterior-pituitary somatotrophs predominantly and almost exclusively. Cloned from rat pituitary cDNA and human pituitary homolog by Mayo, Mol Endocrinol 1992, 6:1734–1744 using PCR-based screening for G-protein-coupled receptors; the receptor's expression pattern is the cleanest single-tissue distribution of any peptide receptor in this atlas. Lower-abundance transcript has been detected in other tissues but does not produce a comparable functional role anywhere outside the somatotroph.

Endogenous ligand. GHRH (growth hormone-releasing hormone), a 44-amino-acid hypothalamic peptide. The molecule was first isolated and sequenced from a pancreatic islet-cell tumor associated with acromegaly by Guillemin et al., Science 1982, 218:585–587; the hypothalamic form was characterized in parallel by Rivier, Spiess, and Vale at the Salk Institute. The full-length 44-mer retains activity, but the N-terminal 1–29 fragment is fully potent at the receptor and is the basis of the GHRH-analog therapeutic class.

Peptides in corpus. Sermorelin is the bare GHRH(1-29) amide — closest in sequence to native human GHRH, brief plasma half-life (~10–20 minutes), produces a sharp GH pulse mirroring the physiological release pattern. Tesamorelin is the full GHRH(1-44) with an N-terminal trans-3-hexenoyl modification that confers DPP-4 resistance; plasma half-life is ~26–38 minutes, and the molecule carries an FDA approval (Egrifta) for HIV-associated lipodystrophy. CJC-1295 is a tetrasubstituted GHRH(1-29) analog (D-Ala², Gln⁸, Ala¹⁵, Leu²⁷); the DAC variant adds a Lys³⁰ maleimidopropionic-acid linker that covalently binds plasma albumin to extend the half-life to 5.8–8.1 days in humans, the longest sustained GH-axis stimulus of any peptide on the site.

Key references. Mayo 1992 (receptor cloning); Guillemin et al. 1982 (GHRH isolation); the receptor-pharmacology layer is filled in across the corpus's GHRH-analog literature, including Falutz et al. 2007 for tesamorelin's pivotal trial, Teichman et al. 2006 for CJC-1295's Phase 1 PK, and Jetté et al. 2005 for the DAC bioconjugate chemistry. The growth-hormone axis dossier walks the comparative pharmacology of the GHRH-R class against GHSR-1a in more detail.

GLP-1R — glucagon-like peptide-1 receptor

Family. Class B (secretin family) G-protein-coupled receptor; Gs-coupled with cAMP / PKA signaling, plus β-arrestin recruitment and biased-agonism profiles that vary across the drug class and are an active subject of pharmacology research.

Tissue distribution. Pancreatic β-cells (the principal glycemic-effect substrate), enteric neurons (slowed gastric emptying), hypothalamic and brainstem neurons (centrally mediated appetite suppression and energy-expenditure modulation; the dominant driver of weight loss), proximal tubule of the kidney, and vascular and cardiac tissues. The β-cell receptor was cloned by Thorens, PNAS 1992, 89:8641–8645 by expression-screening of a rat pancreatic-islet cDNA library; the receptor binds GLP-1 with high affinity and selectivity over glucagon, GIP, VIP, and secretin.

Endogenous ligand. Glucagon-like peptide-1 (GLP-1), an incretin hormone produced by intestinal L-cells. The physiologically active forms are GLP-1(7-36)NH₂ and GLP-1(7-37); both are rapidly inactivated by dipeptidyl peptidase-4 (DPP-4) with a plasma half-life of approximately two minutes, which is the constraint every modern long-acting drug in this class is engineered around.

Peptides in corpus. Semaglutide (GLP-1 monoagonist; FDA-approved for type 2 diabetes and chronic weight management); Liraglutide (the predecessor GLP-1 monoagonist; FDA-approved 2010 for T2D and 2014 for obesity); Tirzepatide (dual GIP/GLP-1 agonist; see also the GIP receptor section below); Retatrutide (investigational triple GIP/GLP-1/glucagon agonist; see also the glucagon receptor section).

Key references. Thorens 1992 (receptor cloning); the trial-grade evidence base for the molecules sits in the GLP-1 receptor pharmacology dossier, which carries Wilding STEP 1, Jastreboff SURMOUNT-1, Frías SURPASS-2, Jastreboff retatrutide Phase 2, Marso SUSTAIN-6, Lincoff SELECT, and the molecular-design papers for semaglutide and tirzepatide. The atlas treats the receptor here briefly because the dossier-length treatment is already in the corpus; readers who want the trial-by-trial walk should go there. This is the deepest pharmacologically characterized single receptor in the entire corpus.

GIP-R — glucose-dependent insulinotropic polypeptide receptor

Family. Class B (secretin family) G-protein-coupled receptor; Gs-coupled with cAMP / PKA signaling on insulin-secreting β-cells.

Tissue distribution. Pancreatic β-cells (glucose-dependent insulin secretion), adipose tissue (insulin sensitization and lipid handling), bone (osteoclast modulation and bone-density signaling), CNS (nausea-pathway interaction, anorectic and energy-expenditure effects), and adrenal cortex. The receptor was cloned by Usdin et al., Endocrinology 1993, 133:2861–2870 and characterized as a member of the secretin-VIP family widely distributed across peripheral organs and the brain — a broader distribution than the somewhat narrower clinical framing of GIP as a pancreatic incretin would suggest.

Endogenous ligand. GIP (glucose-dependent insulinotropic polypeptide; originally gastric inhibitory polypeptide), a 42-amino-acid incretin secreted by intestinal K-cells in response to meal ingestion. GIP and GLP-1 together account for the majority of the incretin effect — meal-stimulated insulin secretion exceeding what would occur from intravenous glucose at matched plasma concentrations.

Peptides in corpus. Tirzepatide is the dual GIP/GLP-1 agonist; the molecule was designed from the native GIP backbone with structural modifications and a C20 fatty diacid for albumin binding, engineered to engage GIP-R and GLP-1R simultaneously (Coskun et al., Mol Metab 2018, 18:3–14). Retatrutide adds glucagon-receptor agonism to the same dual-incretin profile. The pharmacological signature of dual versus mono incretin agonism is the unique contribution Tirzepatide brought to the class — additional metabolic effects on adipose insulin sensitivity, plausible attenuation of nausea-pathway signaling, and head-to-head trial advantage over semaglutide monoagonism in the SURPASS-2 readout.

Key references. Usdin et al. 1993 (receptor cloning); Coskun et al. 2018 (tirzepatide design); Frías et al. 2021 (the head-to-head trial whose result is the cleanest comparative dual-vs-mono evidence the class has produced). The GLP-1 receptor pharmacology dossier carries the broader treatment of how GIP-R engagement reshapes the pharmacology of the incretin-receptor class.

Glucagon receptor — GCGR

Family. Class B (secretin family) G-protein-coupled receptor; Gs-coupled to cAMP / PKA, with secondary coupling to intracellular calcium mobilization. The receptor was cloned by Jelinek et al., Science 1993, 259:1614–1616 using expression cloning against radiolabeled glucagon.

Tissue distribution. Hepatocytes predominantly (the principal site of glycogenolysis and gluconeogenesis activation), kidney, adipose tissue, heart, and brain. Hepatic glucagon-receptor agonism increases endogenous glucose output, which is the canonical physiological effect of native glucagon and the classical objection to therapeutic glucagon-receptor agonism in diabetic populations. Adipose and energy-expenditure effects — including thermogenesis and lipid mobilization — are the metabolic upside the triple-agonist class is designed to exploit while keeping the glucose-output side in balance.

Endogenous ligand. Glucagon, a 29-amino-acid peptide secreted by pancreatic α-cells in response to falling plasma glucose. Glucagon is the canonical counter-regulatory hormone to insulin and is structurally related to GLP-1 (both derive from preproglucagon by alternative tissue-specific processing).

Peptides in corpus. Retatrutide is the only peptide on this site that engages the glucagon receptor — as one of three receptors in its triple GIP/GLP-1/glucagon agonist profile. The pharmacological balance is engineered: glucagon agonism contributes increased energy expenditure and hepatic lipid mobilization, GIP and GLP-1 agonism reduce caloric intake and provide glucose-dependent insulin secretion to counterbalance glucagon's glucose-output effect. Whether the balance is maintainable in chronic dosing — particularly at higher doses where the glucagon component is most active — is the principal open mechanistic question that Phase 3 trials are designed to answer.

Key references. Jelinek et al. 1993 (receptor cloning); Jastreboff et al. 2023 (retatrutide Phase 2 trial); the broader pharmacology context sits in the GLP-1 receptor pharmacology dossier. The glucagon receptor is the third leg of the modern triple-agonist class and the leg with the least precedent in chronic clinical exposure — Phase 3 readouts will substantially update what this section can say about chronic safety.

Melanocortin receptors — MC1R, MC2R, MC3R, MC4R, MC5R

Family. Class A G-protein-coupled receptors, predominantly Gs-coupled with cAMP / PKA signaling. The five-receptor family was cloned in a rapid sequence beginning with Mountjoy, Robbins, Mortrud, and Cone, Science 1992, 257:1248–1251 — which identified MC1R (the melanocyte / α-MSH receptor) and MC2R (the adrenocortical / ACTH receptor) — followed by the MC3R, MC4R, and MC5R clonings by the Cone group and others over the next several years. The receptor subtype family is unusual in that all five subtypes recognize derivatives of the same proopiomelanocortin (POMC) precursor (ACTH, α-MSH, β-MSH, γ-MSH), with subtype selectivity coming from receptor-side rather than ligand-side specificity.

Tissue distribution. MC1R: melanocytes (pigmentation), keratinocytes, leukocytes (anti-inflammatory). MC2R: adrenal cortex zona fasciculata and zona reticularis (cortisol secretion; activated only by ACTH, not the MSH peptides). MC3R: hypothalamus, limbic regions, placenta, gut, kidney (energy homeostasis, inflammation). MC4R: hypothalamic paraventricular nucleus and other forebrain regions (food intake, energy expenditure, sexual function, autonomic regulation). MC5R: exocrine glands, sebaceous glands, skeletal muscle, immune cells.

Endogenous ligands. α-MSH (13 amino acids) and ACTH (39 amino acids; the active N-terminal 1–24 fragment), plus β-MSH and γ-MSH, all cleaved from POMC. The endogenous antagonist agouti-related protein (AgRP) is functional at MC3R and MC4R and is the AgRP-neuron output that opposes α-MSH-driven satiety signaling.

Peptides in corpus. PT-141 / Bremelanotide is a cyclic heptapeptide melanocortin-receptor agonist with preferential MC4R activity and converging contributions from MC3R; FDA-approved (Vyleesi, 2019) for premenopausal acquired generalized hypoactive sexual desire disorder. The mechanism routes through central MC4R-mediated dopamine release in the medial preoptic area and paraventricular nucleus, the pathway that regulates appetitive sexual behavior — distinct from peripheral PDE5-inhibitor action on the vasculature of erectile tissue. KPV — the C-terminal tripeptide of α-MSH (Lys-Pro-Val) — has anti-inflammatory activity through NF-κB suppression; importantly, the colitis-protective effect was preserved in MC1R-null mice in Kannengiesser et al. 2008, ruling out melanocortin-receptor-mediated activity at the gut level (where the mechanism appears to route through PepT1-mediated uptake instead — see PepT1 section). Semax, an ACTH(4-7)-Pro-Gly-Pro heptapeptide, retains some melanocortin-receptor-substrate identity through its ACTH-fragment lineage but the dominant CNS effects appear to operate through opioidergic and BDNF / monoaminergic mechanisms rather than direct MC-receptor pharmacology.

Melanotan I (afamelanotide; approved in EU and Australia as Scenesse for erythropoietic protoporphyria) and Melanotan II are broad melanocortin-receptor agonists used in gray-market tanning markets and for combined tanning-and-libido effects; neither has a peptide page in this corpus, and the standing safety concerns about Melanotan II — particularly the pigmented-lesion changes, atypical-mole development, and the case reports of melanoma in chronic high-dose users — are the principal cautions for any unsupervised melanocortin-agonist use beyond the labeled indications.

Key references. Mountjoy et al. 1992 (receptor family cloning); Huszar et al., Cell 1997, 88:131–141 (MC4R knockout obesity in mice, which anchored the modern feeding-circuit framing); Vaisse et al., Nat Genet 1998, 20:113–114 and Yeo et al., Nat Genet 1998, 20:111–112 (human MC4R loss-of-function obesity, the foundation of monogenic obesity genetics); Brzoska et al., Endocrine Rev 2008, 29:581–602 (α-MSH and tripeptides anti-inflammatory mechanism review); Pfaus et al. 2004 (foundational PT-141 mechanism); Kingsberg et al. 2019 (RECONNECT pivotal Phase III). After GLP-1R, the melanocortin receptors are the second most deeply pharmacologically characterized family in the corpus.

GHR and IGF-1R — growth hormone receptor and IGF-1 receptor

Family. GHR: type I cytokine receptor family, JAK2 / STAT5 signaling (not a GPCR; receptor dimerization triggers tyrosine-kinase recruitment and phosphorylation cascade). IGF-1R: receptor tyrosine kinase, with intrinsic kinase activity and PI3K/Akt and Ras/MAPK downstream pathways — structurally related to the insulin receptor.

Tissue distribution. GHR: liver predominantly (where it drives IGF-1 production), plus most peripheral tissues including muscle, adipose, bone, and immune cells. IGF-1R: ubiquitously expressed; the principal mediator of the somatomedin / growth-promoting effects of the GH axis.

Endogenous ligands. GH (22 kDa, 191 amino acids; pituitary somatotroph product); IGF-1 (insulin-like growth factor 1; 70 amino acids; principally hepatic with paracrine production in many tissues).

Peptides in corpus. None of the peptides in this corpus bind GHR or IGF-1R directly. The entire GH-secretagogue class — Sermorelin, Tesamorelin, CJC-1295 (all GHRH-R agonists); Ipamorelin, Hexarelin (GHSR-1a agonists); MK-677 (GHSR-1a non-peptide agonist) — produces its clinical effects downstream through GH release and subsequent hepatic IGF-1 production acting on these receptors. This is the receptor-pharmacology reason every GH-axis intervention shares the same class-level cancer caution (IGF-1 is mitogenic for many tumor types), the same fluid-retention and carpal-tunnel signal at higher doses, and the same glycemic-shift concern over chronic exposure. The receptor pharmacology of GHR and IGF-1R themselves is not directly modulated by peptides on this site, but is the substrate on which every GH-secretagogue effect lands.

Key references. GH-axis receptor pharmacology is well-characterized in the broader endocrinology literature; for the corpus-relevant subset, see the growth-hormone axis dossier, which walks the pulsatile-versus-tonic GH/IGF-1 signaling distinction and its safety implications. The point of including GHR and IGF-1R in this atlas is to make explicit that the GH-secretagogue class is not directly receptor-pharmacologically modulating these targets — but is producing its clinical effects through them, which has implications for how chronic dosing should be framed.

VEGFR2 / eNOS-NO axis

Family. VEGFR2 (KDR / Flk-1): receptor tyrosine kinase, intrinsic kinase activity, downstream PI3K/Akt and Ras/Raf/MEK/ERK signaling. eNOS (endothelial nitric oxide synthase): cytosolic / membrane-associated enzyme producing NO from L-arginine; not a receptor but a coupled downstream effector. The VEGFR2-Akt-eNOS cascade is one of the canonical angiogenic-signaling pathways and is the principal route by which vascular endothelial growth factor drives neovascularization.

Tissue distribution. Vascular endothelial cells (the principal substrate for angiogenesis), with VEGFR2 also expressed on hematopoietic cells, retinal cells, and a subset of tumor cells. eNOS is expressed in vascular endothelium, cardiomyocytes, platelets, and several other tissue types.

Endogenous ligand. For VEGFR2: VEGF-A (the dominant angiogenic isoform), VEGF-C and VEGF-D (lymphatic-axis ligands), and additional VEGF-family members. For eNOS: L-arginine is the substrate; activation is triggered by VEGFR2 → PI3K → Akt phosphorylation of eNOS at Ser1177, by shear stress, and by Ca²⁺-calmodulin binding.

Peptides in corpus. BPC-157 is the peptide on this site with the most explicit mechanistic anchoring to the VEGFR2-eNOS-NO axis. The cytoprotection model developed by Sikiric's Zagreb group routes BPC-157's tissue-repair activity through vascular recruitment — activating vessels to reach injury sites and opening collateral circulation when the primary route is blocked. The most explicit receptor-level mechanism paper is Hsieh et al., J Mol Med 2017, 95:323–333, which showed that BPC-157 promotes VEGFR2 internalization in vascular endothelial cells (a process blocked by the endocytosis inhibitor dynasore) and time-dependently activates VEGFR2-Akt-eNOS signaling, increasing vessel density both in vivo and in vitro and accelerating blood-flow recovery in rat hind-limb ischemic muscle. The 2018 Sikiric et al. review synthesizes the broader cytoprotective vascular framing.

Key references. Hsieh et al. 2017 (BPC-157 VEGFR2 internalization mechanism); Sikiric et al. 2018 (cytoprotective vascular synthesis); Vukojevic et al. 2020 (NO-system shift in cerebral ischemia). The receptor-level mechanism is single-laboratory in origin (the Hsieh paper is from Taipei Medical University, independent of the Zagreb group, which is methodologically important) but the broader BPC-157 evidence base is concentrated in Sikiric's lab — the standard caveat that applies to nearly every BPC-157 mechanistic claim. The healing and angiogenesis dossier walks the broader VEGFR2-eNOS-NO axis context for the healing-peptide class.

CD36 — scavenger receptor B2

Family. Class B scavenger receptor; an 88-kDa transmembrane glycoprotein that recognizes a diverse ligand set including thrombospondin, oxidized LDL, long-chain fatty acids, and Plasmodium-infected erythrocytes. CD36 is not classically considered a signaling receptor in the canonical sense but does activate downstream Src-family kinase / MAPK signaling and modulates fatty-acid uptake in cardiomyocytes and adipocytes.

Tissue distribution. Cardiomyocytes (the tissue most relevant to the hexarelin literature), microvascular endothelial cells, adipocytes, platelets, macrophages, and skeletal-muscle cells. CD36's role in fatty-acid handling is its dominant physiological function; the GHRP-binding role identified by Bodart is anatomically distinct from the pituitary GHSR-1a binding that drives the GH-release effect.

Endogenous ligand. Thrombospondin-1, oxidized LDL, and long-chain fatty acids are the principal native ligands. Hexarelin is exogenous to this physiology — it binds CD36 as an off-target relative to its primary GHSR-1a pharmacology, and the binding is what makes hexarelin's cardiology profile distinct from every other GHRP.

Peptides in corpus. Hexarelin is the only peptide on this site with characterized CD36 binding. The molecular identification is anchored in Bodart et al., Circulation Research 2002, 90:844–849, which used a radioactive photoactivatable derivative of hexarelin on rat cardiac membranes to identify the binding protein as CD36, and showed that hexarelin's coronary-perfusion-pressure effect was abolished in CD36-null mice and in CD36-deficient spontaneously hypertensive rats. The cardiac effects characterized in Bisi et al. 1999 (acute LVEF increase in healthy male volunteers) and Locatelli et al. 1999 (cardioprotection in hypophysectomized rats incapable of producing GH) are mechanistically anchored to this binding rather than to the GH-release pathway. Ipamorelin, notably, does not engage CD36; the cardiac literature on Ipamorelin is correspondingly thinner.

Key references. Bodart et al. 2002 (CD36 identification by photoaffinity cross-linking); the broader hexarelin cardiac literature is summarized on the hexarelin peptide page. The CD36 cardiac-binding mechanism is mechanistically distinct from any other receptor on this list — the only "scavenger receptor" entry in the corpus — and the molecular evidence is high-quality but the trial-scale cardiology data hexarelin produced never matured into a regulator-grade indication.

IRR — innate repair receptor (CD131 + EPOR heterodimer)

Family. Heteromeric cytokine receptor complex composed of the erythropoietin receptor (EPOR; type I cytokine receptor) and the common β-receptor / CD131 / βcR (which is shared with the GM-CSF, IL-3, and IL-5 receptor systems). Distinct from the homodimeric (EPOR)₂ receptor that mediates hematopoiesis: the IRR carries EPO's tissue-protective and anti-inflammatory signaling without the erythropoietic effect.

Tissue distribution. Upregulated in tissues under hypoxic, ischemic, or inflammatory stress — the receptor system appears as a compensatory response rather than at constitutive baseline levels. Documented across multiple tissue contexts: peripheral nerve (relevant to neuropathy indications), retina, kidney, heart, brain, vascular endothelium. The temporal pattern of upregulation — a characteristic delay after the initial injury — is part of why the IRR-targeted therapy was framed as targeting the "wounded tissue" rather than healthy tissue.

Endogenous ligand. Erythropoietin itself, which engages both the homodimeric (EPOR)₂ for hematopoiesis and the heterodimeric IRR for tissue protection through distinct binding interfaces on the same hormone.

Peptides in corpus. ARA-290 / Cibinetide is the 11-amino-acid peptide (pyroE-EQLERALNSS) engineered to reproduce the aqueous face of helix B of human EPO while stripping away every residue that contacts the homodimeric EPO receptor — preserving the IRR-binding face but not the dimerization interface required for (EPOR)₂ activation. The molecule is the rare design success in which receptor decoupling was achieved: ARA-290 retains the tissue-protective and anti-inflammatory activity of EPO without raising hematocrit or producing erythropoietic side effects. The clinical-development program produced legitimate Phase II signals across small-fiber neuropathy associated with sarcoidosis and diabetic peripheral neuropathy, and then stalled commercially — there is no active sponsor-led Phase III trial for any indication.

Key references. Brines et al., PNAS 2008, 105:10925–10930 (foundational helix B / tissue-protective design paper); Brines and Cerami, Mol Med 2012, 18:486–496 (IRR synthesis review); Ueba et al., PNAS 2010, 107:14357–14362 (helix B surface peptide in heart-failure model); the Phase II clinical evidence sits across the Heij 2012, Dahan 2013, Brines 2015, and Culver 2017 trials cited on the ARA-290 peptide page. The IRR is one of the thinnest characterized receptor systems in the corpus — only two laboratories have produced most of the world's primary literature on the heterodimeric complex, and the receptor's structural biology is less mature than the GLP-1R or melanocortin-receptor structures. The mechanism story is elegant; the clinical-development depth is limited.

BDNF receptor (TrkB) and HGF / c-Met system

Family. TrkB (NTRK2): receptor tyrosine kinase; binds BDNF and NT-4 with high affinity, activates PLCγ, PI3K/Akt, and MAPK/ERK pathways downstream. c-Met (MET): receptor tyrosine kinase; binds hepatocyte growth factor (HGF), activates Gab1 / Grb2 / PI3K / MAPK signaling cascades, drives dendritic outgrowth and synapse formation in the developing and adult brain.

Tissue distribution. TrkB: CNS predominantly, with peak expression in hippocampus, cortex, basal forebrain, and several other regions; the principal mediator of activity-dependent synaptic plasticity. c-Met: brain (developmental peak in P7–P14 perinatal period with persisting adult expression in dendritic-outgrowth contexts), liver, kidney, lung, and a substantial fraction of solid tumors where c-Met dysregulation drives tumor growth, metastasis, and therapy resistance.

Endogenous ligands. BDNF (brain-derived neurotrophic factor; 247-amino-acid precursor cleaved to a 119-amino-acid mature peptide) for TrkB; HGF (a 92-kDa heterodimeric protein) for c-Met.

Peptides in corpus. Semax is reported to upregulate BDNF protein and BDNF / TrkB transcriptional signaling in hippocampus and basal forebrain; the relationship is downstream rather than direct (Semax does not bind TrkB), with the mechanism appearing to route through melanocortin-substrate and monoaminergic effects that converge on neurotrophin expression. Dihexa is the corpus peptide most directly linked to c-Met — the Harding-lab mechanistic framing proposes that Dihexa potentiates HGF activity at c-Met, driving PI3K/Akt signaling, dendritic spine formation, and synaptogenesis. The "10 million times more potent than BDNF" potency headline that has propagated through the marketing literature traces specifically to a cell-culture synaptogenesis assay in McCoy et al. 2013, which carries a Journal of Pharmacology and Experimental Therapeutics Expression of Concern since September 2021, and the broader Wright/Harding-lab corpus has suffered two formal retractions of closely related papers in April 2025. The most-directly-relevant clinical descendant — Athira Pharma's fosgonimeton (Hua et al. 2022) — failed its pivotal LIFT-AD trial in 2025. The HGF/c-Met cancer-mechanism caution is substantive: c-Met dysregulation is documented across gastric, hepatocellular, lung, and colorectal cancers, which is the load-bearing reason cancer history is a serious contraindication for any c-Met-pathway agent.

Key references. McCoy et al. 2013 (Dihexa design/characterization; carries Expression of Concern); Hua et al. 2022 (fosgonimeton Phase 1); jpet-2025-dihexa-retraction-landscape (corpus-integrity catalog). The TrkB receptor pharmacology related to Semax is downstream-effect characterization rather than direct receptor binding; the c-Met-targeting story for Dihexa rests on a corpus from a single laboratory whose source papers carry unresolved research-integrity questions. Of the receptor systems on this list, BDNF/TrkB and HGF/c-Met sit in the unusual position of having well-characterized canonical pharmacology in the broader neuroscience literature, paired with weak peptide-corpus engagement (Semax's BDNF effect is downstream; Dihexa's c-Met effect is from a corpus with serious integrity questions).

GABA-A receptor (allosteric site)

Family. Ionotropic GABA receptor: pentameric ligand-gated chloride channel composed typically of two α, two β, and one γ (or other) subunit. Activation by GABA opens the chloride channel, hyperpolarizing the neuron and producing the inhibitory postsynaptic potential. Several pharmacologically distinct binding sites — benzodiazepine site, barbiturate site, neurosteroid site, picrotoxin site, the GABA-binding orthosteric site itself — produce different functional outcomes when modulated, and the canonical psychiatric drug classes (benzodiazepines, barbiturates, propofol, several anticonvulsants) operate through this allosteric architecture.

Tissue distribution. CNS predominantly; the receptor is the principal inhibitory neurotransmitter receptor in the mammalian brain, expressed across cortex, hippocampus, cerebellum, amygdala, and most other regions, with subunit composition varying by region and developmental stage.

Endogenous ligand. GABA (γ-aminobutyric acid), produced by glutamate decarboxylase (GAD) in inhibitory interneurons throughout the CNS.

Peptides in corpus. Selank is the peptide on this site with the most explicit GABA-A receptor characterization. The mechanism is reframed by Volkova et al., Front Pharmacol 2016, 7:31 — in rat frontal cortex, a single intranasal 300 µg/kg Selank dose produced a 1-hour gene-expression signature with strong positive correlation (Pearson's r = 0.86) to GABA's own expression-change pattern across an 84-gene array, consistent with positive allosteric modulation of the GABAergic system. At 3 hours the patterns diverged, with Selank uniquely driving a 128-fold increase in hypocretin (Hcrt) expression alongside reversal of early downregulation of GABA-A receptor epsilon (16-fold up) and theta (13-fold up) subunits. The follow-up Filatova et al. 2017 showed in human IMR-32 neuroblastoma cells that Selank alone produced no change in GABAergic gene expression but modulated the response of those genes to GABA or olanzapine — consistent with allosteric co-modulation rather than direct orthosteric ligand activity. Unlike benzodiazepines, Selank does not appear to bind the canonical benzodiazepine site directly; the receptor engagement is allosteric and at non-classical sites, which is the hypothesis underlying the reported non-sedating, non-dependency-forming profile.

Key references. Volkova et al. 2016 (primary GABAergic gene-expression characterization); Filatova et al. 2017 (cell-line follow-up); Zozulya et al. 2008 (clinical anxiolytic RCT vs medazepam). The GABA-A receptor pharmacology in the broader literature is one of the most deeply characterized of any ligand-gated channel; the Selank-specific allosteric site has not been definitively localized at the receptor-structure level, which is a real gap. The mechanism case is internally consistent with the clinical anxiolytic signal, but the precise binding site remains the open question.

PepT1 — proton-coupled oligopeptide transporter

Family. Solute carrier family 15, member 1 (SLC15A1); a proton-coupled di- and tripeptide transporter rather than a receptor in the canonical signaling sense. Transport activity is driven by an inward proton gradient and produces electrogenic uptake of di- and tripeptide substrates into the cell.

Tissue distribution. Small intestine epithelium (the principal physiological substrate for dietary peptide absorption), upregulated on inflamed colonic epithelium in inflammatory bowel disease (the mechanistically relevant property for KPV's targeting), kidney proximal tubule (reabsorption of filtered peptides), and immune cells in inflamed tissue.

Endogenous ligand / substrates. PepT1 transports a broad range of di- and tripeptides — both dietary protein-digestion products and many small peptide pharmaceuticals (β-lactam antibiotics, ACE inhibitors, valacyclovir). The transporter's substrate breadth is what enables it to function as the carrier for orally administered short peptides that would not otherwise cross the intestinal epithelium intact.

Peptides in corpus. KPV — the α-MSH(11-13) tripeptide — is the corpus peptide with the most explicit PepT1 mechanism characterization. The mechanism is anchored in Dalmasso et al., Gastroenterology 2008, 134:166–178, which showed that KPV enters epithelial and immune cells through PepT1 and produces anti-inflammatory effects at nanomolar concentrations through NF-κB and MAP-kinase pathway suppression. The mechanism is preserved in MC1R-non-functional mice (Kannengiesser et al. 2008), ruling out melanocortin-receptor-mediated activity at the gut level. The PepT1 mechanism is the structural reason oral KPV is a credible IBD-targeted concept — PepT1 expression is upregulated on inflamed colonic epithelium, which concentrates the tripeptide preferentially at sites of disease. Whether the same mechanism supports oral systemic bioavailability for indications outside the gut is less clear.

Key references. Dalmasso et al. 2008 (PepT1-mediated KPV uptake and colitis attenuation); Kannengiesser et al. 2008 (MC1R-independence confirmation); Xiao et al. 2017 (nanoparticle-delivery 12,000-fold concentration advantage). PepT1 is unusual on this atlas in that it is a transporter rather than a signaling receptor — included because it is the molecular structure that determines KPV's tissue targeting and oral-bioavailability claim, both of which are central to how the peptide is used clinically.

NPY-Y2 — neuropeptide Y receptor type 2

Family. Class A G-protein-coupled receptor, Gi/o-coupled with adenylyl cyclase inhibition and downstream MAPK signaling. The NPY receptor family (Y1, Y2, Y4, Y5, y6) recognizes NPY, peptide YY (PYY), and pancreatic polypeptide (PP) with subtype-specific affinity profiles.

Tissue distribution. Hypothalamic arcuate nucleus (presynaptic autoreceptor on NPY/AgRP neurons), brainstem nucleus tractus solitarius, gastrointestinal tract, sympathetic nerve terminals. NPY-Y2 sits in the same hypothalamic appetite circuit that MC3R/MC4R modulate, integrating peripheral hormone signals (PYY released from intestinal L-cells postprandially is a high-affinity Y2 agonist) with central feeding regulation.

Endogenous ligand. PYY(3-36) is the principal endogenous Y2 agonist; the truncated form is produced from PYY(1-36) by DPP-4 cleavage and is selectively active at Y2 versus the broader-affinity Y1 / Y5 receptors. NPY itself is also a Y2 substrate but with lower selectivity.

Peptides in corpus. None of the peptides on this site directly engage NPY-Y2 as their primary mechanism. The receptor appears here for context: the incretin-class molecules (semaglutide, tirzepatide, retatrutide) modulate feeding and satiety partially through downstream interactions with the hypothalamic NPY/AgRP and POMC neurons that NPY-Y2 also helps regulate. The next-generation obesity-pharmacology pipeline that will reach the clinic over the late 2020s and into the 2030s is likely to include PYY-analog or NPY-Y2-selective agents alongside the incretin-class drugs, which is one of the reasons the receptor is worth flagging in this atlas even though it does not yet have a corpus-peptide assignment.

Key references. Foundational receptor characterization sits in the broader appetite-regulation literature (Batterham, Bloom, and colleagues' PYY(3-36) work in the early 2000s; the NPY-Y receptor cloning chronology across the 1990s). The reason the receptor appears in this atlas is forward-looking: as the corpus expands to track the next-generation incretin and incretin-adjacent pipeline, the NPY-Y2 / Y4 / Y5 receptor entries will plausibly need to grow, and flagging the receptor now anchors that future structure.

Pineal axis / MT1 and MT2 melatonin receptors

Family. MT1 (MTNR1A) and MT2 (MTNR1B): class A G-protein-coupled receptors, predominantly Gi/o-coupled with adenylyl cyclase inhibition. MT1 was cloned by Reppert, Weaver, and Ebisawa, Neuron 1994, 13:1177–1185; MT2 (the Mel1b receptor) was characterized by Reppert et al., PNAS 1995, 92:8734–8738.

Tissue distribution. MT1: suprachiasmatic nucleus (circadian phase-setting), pars tuberalis of the pituitary, retina, several brain regions, vascular smooth muscle. MT2: retina, brain (different regional pattern from MT1), with chromosomal locus mapped to 11q21-22.

Endogenous ligand. Melatonin (N-acetyl-5-methoxytryptamine), produced principally by the pineal gland from serotonin under nocturnal cues, secreted in a circadian pattern that anchors the body's main daylength signal. Peripheral melatonin production also occurs in retina, gut, immune cells, and other tissues, but the systemic pulse is principally pineal.

Peptides in corpus. Epitalon — the AEDG tetrapeptide derived from the bovine pineal-extract Epithalamin — is the corpus peptide most associated with pineal-axis claims. The framing in the Khavinson program is that the tetrapeptide modulates pineal function and restores melatonin-axis homeostasis in aging tissues. The receptor-level pharmacology is not characterized at the same depth as for any other peptide in this atlas. No published primary literature shows direct Epitalon binding to MT1 or MT2 melatonin receptors at any physiologically relevant affinity. The mechanism that is characterized — telomerase induction in cell culture (Khavinson et al. 2003) and the in-silico DNA-binding hypothesis (Khavinson et al. 2013) — is not a receptor mechanism in the canonical signaling sense. The "pineal-modulating" framing should be read as a phenotypic observation (the parent extract was derived from the pineal, the molecule emerges from a pineal-peptide research lineage, and the framing is partly derivational rather than direct receptor pharmacology). This is honest framing: of all the receptor entries in this atlas, the pineal axis is the one where the molecular-pharmacology evidence is thinnest for the peptide that claims it.

Key references. Reppert et al. 1994 (MT1 cloning); Reppert et al. 1995 (MT2 cloning); Khavinson et al. 2003 (Epitalon telomerase mechanism — not a receptor mechanism); Khavinson et al. 2013 (DNA-binding hypothesis — in silico, no cellular DNA-occupancy confirmation). The /critic/telomere-anti-aging-overstatement response addresses how the marketing framing of Epitalon overstates the cellular telomerase data; the anti-aging decision guide walks where the molecule sits in the broader longevity-pharmacology landscape.

Mitochondrial inner membrane / cardiolipin (target, not receptor)

Target. Cardiolipin is a unique phospholipid (1,3-bis(sn-3'-phosphatidyl)-sn-glycerol) concentrated almost exclusively in the inner mitochondrial membrane, where it organizes electron-transport-chain supercomplexes and stabilizes cristae morphology. Cardiolipin is a binding target rather than a signaling receptor — there is no canonical receptor-pharmacology G-protein cascade involved. This entry is included in the atlas because two molecules on the site operate through fundamentally non-receptor mechanisms that warrant explicit treatment.

Tissue distribution. Mitochondria-rich tissues: cardiomyocytes, skeletal muscle (particularly slow-fiber oxidative myofibers), kidney proximal tubule, neurons, hepatocytes. Cardiolipin peroxidation under oxidative stress disrupts cristae structure and respiratory-chain efficiency, which is the cellular pathology that SS-31's pharmacology is designed to address.

Peptides in corpus. SS-31 / Elamipretide is the corpus peptide that binds cardiolipin directly. The molecule (D-Arg-2',6'-dimethylTyr-Lys-Phe-NH₂) was engineered by Hazel Szeto and Peter Schiller at Cornell to combine alternating aromatic and basic residues with a D-stereochemistry N-terminal arginine that produces 1,000- to 5,000-fold concentration in the inner mitochondrial membrane through electrostatic and hydrophobic interactions with the negatively-charged cardiolipin headgroup. The mechanism is refined in Mitchell et al., J Biol Chem 2020, 295:7452–7469: binding is mediated by surface electrostatics on cardiolipin rather than a simple lipid-binding-pocket model, with implications for how the molecule should be understood pharmacologically. The cellular phenotype — improved mitochondrial respiration, reduced ROS production under stress, preserved cristae morphology — has been characterized across ischemia-reperfusion, heart-failure, and primary mitochondrial-disease models.

MOTS-c acts on mitochondrial biology through an entirely different mechanism: it is a 16-amino-acid peptide encoded within the mitochondrial 12S ribosomal RNA gene (MT-RNR1), discovered by Lee et al., Cell Metab 2015, 21:443–454, that inhibits the folate cycle and raises AICAR levels, activating AMP-activated protein kinase (AMPK). MOTS-c does not bind cardiolipin, does not act on the inner mitochondrial membrane structurally, and is not a receptor agonist in the canonical sense — it functions as an endocrine-like signaling peptide of mitochondrial origin, with skeletal muscle as the principal tissue target.

Key references. For SS-31: Birk et al., J Am Soc Nephrol 2013, 24:1250–1261 (foundational cardiolipin binding and renal ischemia model); Mitchell et al. 2020 (lipid-bilayer mechanism refinement); Karaa et al. MMPOWER-2 and MMPOWER-3 for the clinical trajectory through to the September 2025 Forzinity approval for Barth syndrome. For MOTS-c: Lee et al. 2015 (discovery and primary characterization); Reynolds et al. 2021 (exercise-induction signaling in humans). The mitochondrial peptides dossier walks the broader class context.

Synthesis: depth-variance and what it tells the reader

The pharmacological characterization of receptors targeted by peptides on this site varies more dramatically than any single peptide page can convey. Pulled together as an atlas, the variance becomes clear:

Deepest characterization. The GLP-1 receptor sits at the top of this list — five years of accumulating large-trial evidence (STEP, SURMOUNT, SURPASS, SELECT, the retatrutide Phase 2 readout) on top of three decades of receptor pharmacology that includes the 1992 Thorens cloning, structural biology, signaling characterization, and molecular-design papers for every approved molecule in the class. Drugs targeting this receptor have produced effect sizes previously confined to bariatric surgery and have shifted the regulatory landscape of obesity pharmacotherapy. The melanocortin-receptor family is the second-deepest characterization in the corpus: five receptor subtypes, distinct tissue distributions, monogenic-obesity genetics (Huszar mouse plus Vaisse and Yeo human MC4R loss-of-function), FDA-approved peptide at MC4R (PT-141 / Vyleesi), and Phase III evidence-base depth at multiple drug programs. The GHRH-receptor and GHSR-1a entries are also well-characterized at the receptor level, though the corpus-relevant peptides have largely stalled at non-pivotal-trial development.

Thinnest characterization. The innate repair receptor (CD131 + EPOR heterodimer) is the most elegantly designed receptor target on this list and the one with the smallest sustained clinical-development program. Two laboratories produced most of the world's primary literature; the receptor's structural biology is less mature than for any GPCR on this atlas; the clinical development of ARA-290 / cibinetide stalled in the late 2010s and has not resumed. CD36 cardiac binding is the second-thinnest — the molecular identification by Bodart is high-quality but the cardiology trial program at hexarelin scale never matured. The pineal-axis / melatonin-receptor entry for Epitalon is the third — the receptor pharmacology of MT1 and MT2 themselves is reasonably well-characterized, but Epitalon's direct receptor engagement is not characterized at all; the "pineal-modulating" framing is partly derivational rather than receptor-pharmacological. The Dihexa / HGF–c-Met case has the additional complication that the foundational mechanism papers from the Wright/Harding laboratory carry an Expression of Concern and two recent retractions, making the receptor-targeting claims harder to read confidently than the broader HGF/c-Met literature would suggest in isolation.

What this tells the reader. Two peptides that engage the GLP-1 receptor (Semaglutide and Tirzepatide) sit on a 10,000-patient pivotal-trial evidence base. Two peptides that engage CD36 (Hexarelin) or the innate repair receptor (ARA-290) sit on Phase 2 or Phase 1 cohort sizes in the dozens. The receptor-pharmacology depth and the clinical-evidence depth are not independent variables — they tend to correlate, because regulator-grade clinical development pushes receptor characterization forward at every stage, and stalled commercial development tends to leave receptor characterization at whatever depth the academic-lab program produced before the sponsor exited.

This is the practical reason the atlas is worth reading alongside any specific peptide page: knowing that the receptor a peptide targets has been characterized at depth X (with N independent laboratories producing primary work, M trial programs running to Phase III, K crystal structures in the PDB) is part of how to read the depth of evidence for any specific clinical claim about the peptide itself. A peptide acting on a deeply characterized receptor with a long clinical-development history rests on a different evidence stack than a peptide acting on a thinly characterized receptor with a single-program development arc. The atlas makes that stack legible at a glance.

The receptor pharmacology under the peptide names is not just decorative context. It is the structural-biology layer on which every claim about every molecule on this site ultimately rests. Where that layer is deep, the claims are correspondingly more constrained by evidence; where it is thin, the claims rest on extrapolation from adjacent systems and from mechanism plausibility rather than from receptor-level confirmation. Reading the corpus through the receptor atlas is one of the more honest framings the site can offer.

Sources cited

External primary citations verified for this atlas:

• Bowers et al., Endocrinology 1984, 114:1537–1545 — GHRP-6 design
• Guillemin et al., Science 1982, 218:585–587 — GHRH isolation from pancreatic tumor
• Mayo, Mol Endocrinol 1992, 6:1734–1744 — GHRH receptor cloning
• Mountjoy et al., Science 1992, 257:1248–1251 — Melanocortin receptor family cloning
• Thorens, PNAS 1992, 89:8641–8645 — GLP-1 receptor cloning
• Jelinek et al., Science 1993, 259:1614–1616 — Glucagon receptor cloning
• Usdin et al., Endocrinology 1993, 133:2861–2870 — GIP receptor cloning
• Reppert et al., Neuron 1994, 13:1177–1185 — MT1 melatonin receptor cloning
• Reppert et al., PNAS 1995, 92:8734–8738 — MT2 melatonin receptor cloning
• Howard et al., Science 1996, 273:974–977 — GHSR cloning
• Huszar et al., Cell 1997, 88:131–141 — MC4R knockout obesity
• Vaisse et al., Nat Genet 1998, 20:113–114 — Human MC4R obesity
• Yeo et al., Nat Genet 1998, 20:111–112 — Human MC4R obesity
• Kojima et al., Nature 1999, 402:656–660 — Ghrelin discovery
• Tschöp et al., Nature 2000, 407:908–913 — Ghrelin appetite and adiposity
• Bodart et al., Circulation Research 2002, 90:844–849 — CD36 hexarelin identification
• Brzoska et al., Endocrine Reviews 2008, 29:581–602 — α-MSH and tripeptides review
• Dalmasso et al., Gastroenterology 2008, 134:166–178 — KPV PepT1 mechanism
• Brines et al., PNAS 2008, 105:10925–10930 — EPO helix B / IRR
• Yang et al., Cell 2008, 132:387–396 — GOAT / ghrelin acylation enzyme
• Brines and Cerami, Mol Med 2012, 18:486–496 — Innate repair receptor synthesis
• Lee et al., Cell Metabolism 2015, 21:443–454 — MOTS-c discovery
• Volkova et al., Frontiers in Pharmacology 2016, 7:31 — Selank GABAergic gene expression
• Hsieh et al., J Mol Med 2017, 95:323–333 — BPC-157 VEGFR2 mechanism
• Coskun et al., Molecular Metabolism 2018, 18:3–14 — Tirzepatide dual-agonist design
• Mitchell et al., J Biol Chem 2020, 295:7452–7469 — SS-31 lipid-bilayer mechanism

In-corpus references cross-linked from this atlas (peptide and research entries) appear inline above and are not duplicated here.