title: Synthesis and evaluation of novel peripherally restricted kappa-opioid receptor agonists.
abstract: A series of 3-substituted analogs (3) of the parent kappa agonist, 1, were prepared to limit access to the central nervous system. With the exception of compound 3j, all other compounds bound to the human kappa opioid receptor with high affinity (K(i)=0.31-9.5 nM) and were selective for kappa over mu and delta opioid receptors. Compounds 3c, d, and 3g-i produced potent antinociceptive activity in the rat formalin assay (i.paw) and the mouse acetic acid-induced writhing assay (s.c.), with weak activity in the mouse platform sedation test. The peripheral restriction indices of 3c, d, 3g, and 3i were improved 2- to 7-fold compared to the parent compound 1, and these compounds were approximately 2- to 5-fold more potent than the peripheral kappa agonist ICI 204448.
authors.affiliation: Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, USA. vkumar@adolor.com
authors.forename: Virendra
authors.initials: V
authors.lastname: Kumar
authors.forename: Deqi
authors.initials: D
authors.lastname: Guo
authors.forename: Joel A
authors.initials: JA
authors.lastname: Cassel
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Daubert
authors.forename: Robert N
authors.initials: RN
authors.lastname: Dehaven
authors.forename: Diane L
authors.initials: DL
authors.lastname: Dehaven-Hudkins
authors.forename: Erin K
authors.initials: EK
authors.lastname: Gauntner
authors.forename: Susan L
authors.initials: SL
authors.lastname: Gottshall
authors.forename: Susan L
authors.initials: SL
authors.lastname: Greiner
authors.forename: Michael
authors.initials: M
authors.lastname: Koblish
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Little
authors.forename: Erik
authors.initials: E
authors.lastname: Mansson
authors.forename: Alan L
authors.initials: AL
authors.lastname: Maycock
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002490:Central Nervous System / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D010146:Pain / Q000188:drug therapy; D017288:Pain Threshold / Q000187:drug effects; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000700:Analgesics; D006575:Heterocyclic Compounds, 3-Ring; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa