Conformationally Constrained Tachykinin Analogues: Potent and Highly Selective Neurokinin NK-2 Receptor Agonists

Article abstract of DOI:10.1021/jm00100a027

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 γ-lactam conformational constraint into the C-terminal region of the neurokinin A octapeptide analogue 3>-NKA(3-10).Compound 31 (EC50 = 15 nM in rat colon) contains a novel fused-bicyclicconstraint at the corresponding site in the substance P hexapeptide analogue 6>-SP(6-11).