title: Nascent structure-activity relationship study of a diastereomeric series of kappa opioid receptor antagonists derived from CJ-15,208.
abstract: 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).
authors.affiliation: Department of Chemistry, Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, USA. rdolle@adolor.com
authors.forename: Roland E
authors.initials: RE
authors.lastname: Dolle
authors.forename: Mathieu
authors.initials: M
authors.lastname: Michaut
authors.forename: Blanca
authors.initials: B
authors.lastname: Martinez-Teipel
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Seida
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Ajello
authors.forename: Alison L
authors.initials: AL
authors.lastname: Muller
authors.forename: Robert N
authors.initials: RN
authors.lastname: DeHaven
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Carroll
mesh_terms: 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
chemical_list: C540936:CJ 15,208; D010456:Peptides, Cyclic; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu