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J Med Chem. 1992 Oct 30;35(22):4195-204.

Conformationally constrained tachykinin analogues: potent and highly selective neurokinin NK-2 receptor agonists.

Author information

1
Medicinal Chemistry Department, Glaxo Group Research, Greenford, Middlesex, UK.

Abstract

The design and synthesis of potent and selective neurokinin NK-2 receptor agonists 12 (GR64349) and 31 are described, together with structure-activity relationships for related analogues. Compound 12 (EC50 = 3.7 nM at NK-2 receptors in the rat colon; selectivity > 1000- and > 300-fold with respect to NK-1 and NK-3 receptors, respectively) was derived by incorporation of a Gly-Leu gamma-lactam conformational constraint into the C-terminal region of the neurokinin A octapeptide analogue [Lys3]-NKA(3-10). Compound 31 (EC50 = 15 nM in rat colon) contains a novel fused-bicyclic constraint at the corresponding site in the substance P hexapeptide analogue [Ava6]-SP(6-11).

PMID:
1331460
DOI:
10.1021/jm00100a027
[Indexed for MEDLINE]

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