Compound monograph
THIQ
THIQ is a nonpeptide small-molecule agonist at the melanocortin-4 receptor, included here as the nonpeptide comparator to the melanocortin peptides.
01
Identity & nomenclature
THIQ is a nonpeptide small-molecule agonist at the melanocortin-4 receptor, included here as the nonpeptide comparator to the melanocortin peptides.
THIQ is ALSO the generic abbreviation for the tetrahydroisoquinoline scaffold, an entire chemical class. The generic scaffold and this defined MC4R agonist are not the same substance, and a name-only search imports unrelated chemistry — at least one supplier listing conflates them. The chlorine in the formula is a covalent aryl chloride, NOT evidence of a hydrochloride salt.
02
Molecular properties
| Molecular formula | C33H41ClN6O2 |
|---|---|
| Molecular mass | 589.18 Da |
| CAS Registry Number | 312637-48-2 |
| PubChem CID | 9938402 |
Not a peptide. A stereodefined tetrahydroisoquinoline-carboxamide with a 4-chlorophenyl-substituted aminoacyl unit and a piperidine bearing cyclohexyl and triazolylmethyl groups, with two R-configured centres. No peptide shorthand should stand in for the structure.
03
Structural characteristics
Alanine-scanning mutagenesis at MC4R shows the nonpeptide agonists depend on residues across several transmembrane helices, while a linear peptide agonist's binding was substantially reduced by only two of the same substitutions — direct evidence that peptide and nonpeptide routes to the same receptor are not equivalent. Chimeric-receptor work identifies conserved residues required for binding and non-conserved residues in the third transmembrane helix contributing to MC4R selectivity. A receptor-bound structure places it alongside peptide agonists in the same complex study. Selectivity was examined in the comparisons tested; that is not the absence of every off-target interaction.
- Two R-configured stereocentres
- Aryl chloride
04
Molecular targets & mechanisms
05
Analytical considerations
High-resolution MS should show the chlorine isotope pattern, which is the quickest confirmation that the halogen is present and covalent. NMR establishes the substituted scaffold and chiral chromatography the two stereocentres. Neither the name THIQ, nor a tetrahydroisoquinoline substructure match, nor a positive MC4R assay establishes identity — the first because the abbreviation is ambiguous, the last because other MC4R agonists give the same response.
06
Verified bibliography
- Interactions of human melanocortin 4 receptor with nonpeptide and peptide agonists.current
Pogozheva ID, Chai BX, Lomize AL, Fong TM, Weinberg DH, Nargund RP, Mulholland MW, Gantz I, Mosberg HI
Biochemistry · 2005-08-30 · Journal Article
- Key amino acid residues in the melanocortin-4 receptor for nonpeptide THIQ specific binding and signaling.current
Yang Y, Cai M, Chen M, Qu H, McPherson D, Hruby V, Harmon CM
Regulatory peptides · 2009-03-20 · Journal Article
- Structural insights into ligand recognition and activation of the melanocortin-4 receptor.current
Zhang H, Chen LN, Yang D, Mao C, Shen Q, Feng W, Shen DD, Dai A, Xie S, Zhou Y, Qin J, Sun JP, Scharf DH, Hou T, Zhou T, Wang MW, Zhang Y
Cell research · 2021-08-25 · Journal Article
10
Methodology & citation verification
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