Structure-activity studies on cysteine-substituted neurokinin A analogs

A complete series of analogs of tyrosine modified neurokinin A ([Tyr(1)]-NK A or [Tyr(0)]-NKA) has been synthesized by substituting each natural residu e with l-Cys. These analogs were tested for their ability to bind recombina nt neurokinin-2 (NK-2) receptor. Substitution of Phe(6) with Cys completely abolished binding of the analog to the receptor. Substitution of residues in the carboxyl-terminal region of the peptide (Met(10), Leu(9), Gly(8), Va l(7)) and Asp(4) with Cys gave reductions in binding affinity of between 23 - and 250-fold. Molecular dynamics simulations of these analogs suggest tha t changes in peptide structure and flexibility are not large contributors t o the losses in receptor binding affinity. Reductions in binding affinity a re therefore more confidently ascribed to losses of peptide-receptor intera ctions. (C) 1999 Elsevier Science Inc. All rights reserved.