Nascent structure-activity relationship study of a diastereomeric series of kappa opioid receptor antagonists derived from CJ-15,208.
Cyclic tetrapeptide c[Phe-pro-Phe-trp] 2, a diastereomer of CJ-15,208 (1), was identified as a potent dual kappa/mu opioid receptor antagonist devoid of delta opioid receptor affinity against cloned human receptors: K(i) (2)=3.8nM (kappa), 30nM (mu); IC(50) ([(35)S]GTPgammaS binding)=140nM (kappa), 21nM (mu). The d-tryptophan residue rendered 2 ca. eightfold and fourfold more potent at kappa and mu, respectively, than the corresponding l-configured tryptophan in the natural product 1. Phe analogs 3-10, designed to probe the effect of substituents on receptor affinity and selectivity, possessed K(i) values ranging from 14 to 220nM against the kappa opioid receptor with mu/kappa ratios of 0.45-3.0. An alanine scan of 2 yielded c[Ala-pro-Phe-trp] 12, an analog equipotent to 2. Agents 2 and 12 were pure antagonists in vitro devoid of agonist activity. Ac-pro-Phe-trp-Phe-NH(2)16 and Ac-Phe-trp-Phe-pro-NH(2)17 two of the eight possible acyclic peptides derived from 1 and 2, were selective, modestly potent mu ligands: K(i) (16)=340nM (mu); K(i) (17)=360nM (mu).
Dolle
Roland E
RE
Department of Chemistry, Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, USA. rdolle@adolor.com
Michaut
Mathieu
M
Martinez-Teipel
Blanca
B
Seida
Pamela R
PR
Ajello
Christopher W
CW
Muller
Alison L
AL
DeHaven
Robert N
RN
Carroll
Patrick J
PJ
D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C540936:CJ 15,208; D010456:Peptides, Cyclic; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu