Salmon calcitonin research analog (CHEMBL2369915)

What this is

This card is a research-grade peptide ligand of the human calcitonin receptor (CTR, gene symbol CALCR), catalogued by ChEMBL as CHEMBL2369915. It is a 32-residue salmon calcitonin (sCT) analog reported by Taylor and colleagues (J. Med. Chem., 2002) as part of a medicinal-chemistry series exploring how conformational constraints and residue substitutions in the middle and C-terminal regions of calcitonin shape receptor potency. It is not a clinical drug and has no approved use — it is a tool compound used to probe how calcitonin engages its receptor.

The sequence stored on this card (CSNLSTCVLGKLSQELNKLHYRTNTGSGT, 29 standard-letter residues) is a simplified text representation of the actual 32-residue molecule. The active compound contains a norleucine (Nle) at position 21, D-proline at positions 23 and 32, and a C-terminal amide; the stored 1-letter sequence omits the non-standard residues and the amide, and the parent salmon-calcitonin-like scaffold also carries a Cys1–Cys7 disulfide that is not visible in the raw string. The full structure is recorded in ChEMBL as HELM PEPTIDE1{C.S.N.L.S.T.C.V.L.G.K.L.S.Q.E.L.N.K.L.H.[Nle].Y.[dP].R.T.N.T.G.S.G.T.[dP].[am]} (Taylor 2002; ChEMBL CHEMBL2369915).

History

The compound was synthesised and characterised by John W. Taylor's group (Rutgers University) together with collaborators at Pharmacia & Upjohn and elsewhere, reported in 2002 in the Journal of Medicinal Chemistry under the title "Side-Chain Lactam-Bridge Conformational Constraints Differentiate the Activities of Salmon and Human Calcitonins and Reveal a New Design Concept for Potent Calcitonin Analogues" (Taylor 2002). The work belonged to a wider programme exploring why salmon calcitonin is substantially more potent at the human calcitonin receptor than the human peptide itself, and what backbone substitutions or constraints could narrow that gap.

The structure–activity relationships in that paper informed later structural and pharmacological work on the receptor, including the X-ray crystal structure of a related truncated salmon calcitonin analog bound to the human CTR ectodomain (Johansson et al., J. Biol. Chem., 2016).

What it does

The calcitonin receptor is a class B (secretin-family) G-protein-coupled receptor expressed prominently on osteoclasts and in the kidney. Activation of CTR by calcitonin inhibits osteoclast-driven bone resorption and contributes to calcium handling — the basis on which salmon calcitonin was historically used to treat Paget's disease of bone and postmenopausal osteoporosis (Hay et al., Br. J. Pharmacol., 2017, IUPHAR Review 25). This analog binds and activates that same receptor with very high potency in cell-based assays (see Evidence).

Because the compound is an experimental tool with no clinical development programme, "what it does" outside the in-vitro assays it was tested in is not established.

Mechanism

CTR couples primarily to Gαs, raising intracellular cAMP and downstream CRE-driven transcription on agonist binding (Hay 2017). In the assays reported by Taylor 2002, this analog acts as a full agonist at the human CTR I1 isoform expressed in cell systems.

Structurally, calcitonin-family peptides engage the receptor in a two-domain "two-site" fashion typical of class B GPCRs: the C-terminal region of the peptide docks into the receptor's extracellular domain, while the N-terminal portion engages the transmembrane bundle to drive signalling. Salmon calcitonin specifically adopts a type II β-turn at residues Gly28–Thr31 in the receptor-bound state, with an N-terminal Cys1–Cys7 disulfide loop that is part of the activation-determining region (Johansson 2016). The non-standard residues in this analog (Nle21, D-Pro23, D-Pro32, C-terminal amide) sit in the region that controls receptor engagement and proteolytic stability in the calcitonin family.

Evidence

• In vitro: Reported binding affinity Ki = 0.069 nM at the human calcitonin receptor (I1 isoform) expressed in HEK293 cells, measured by displacement of [125I]-salmon calcitonin (Taylor 2002; ChEMBL assay CHEMBL654175). In a functional CRE-luciferase reporter assay in human neuroblastoma cells expressing the same receptor isoform, the analog produced an ED50 of 0.046 nM and showed approximately 250% the relative potency of salmon calcitonin in the same system (ChEMBL assays CHEMBL654174 / CHEMBL654537).
• Animal: No animal data attached to this card.
• Human: No human studies. This compound has not entered clinical development.

Regulatory status

• US / EU: Not an approved drug; research compound only. No FDA or EMA filing.
• WADA: Not specifically listed; the parent class (calcitonin) is not on the current WADA Prohibited List.
• Note on the receptor class: Salmon calcitonin itself was approved for Paget's disease and osteoporosis but its clinical use has declined over time on efficacy, cost-effectiveness, and safety grounds (Hay 2017). Pramlintide, which acts at CTR–RAMP (amylin) complexes rather than at CTR alone, is approved for insulin-requiring diabetes (Hay 2017).

Related peptides

This is a research analog rather than a member of a curated peptide family on the platform, so related-card linkage is limited. It is structurally and pharmacologically related to:

• Salmon calcitonin (sCT) — the parent scaffold; the in-vitro reference compound for this analog's potency measurements.
• Human calcitonin (hCT) — the endogenous human ligand for CTR; substantially less potent than sCT at the human receptor.
• Pramlintide — amylin analog acting at CTR–RAMP (amylin) receptor complexes; the only approved drug pharmacologically related to the calcitonin family used in metabolic disease.
• CGRP, amylin, adrenomedullin — members of the wider calcitonin/CGRP peptide family that share the CTR/CLR receptor system in different RAMP combinations (Hay 2017).