Non-peptide ligands for opioid receptors. Design of .kappa.-specific agonists

A series of phenyl carboxyl esters 5a-d derived from N-(cyclopropylmethyl)normetazocine was synthesized and evaluated for its selectivity at mu, kappa, and delta opioid receptors. Compound 5a, although 43 times less potent than the reference compound U50488, was specific for kappa receptors, having...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1993-06, Vol.36 (13), p.1860-1865
Main Authors: Ronsisvalle, G, Pasquinucci, L, Pappalardo, M. S, Vittorio, F, Fronza, G, Romagnoli, C, Pistacchio, E, Spampinato, S, Ferri, S
Format: Article
Language:English
Subjects:
Animals
Brain - metabolism
Chemistry
Cyclazocine - analogs & derivatives
Cyclazocine - chemical synthesis
Cyclazocine - metabolism
Cyclazocine - pharmacology
Drug Design
Esters - chemical synthesis
Esters - pharmacology
Exact sciences and technology
Guinea Pigs
Heterocyclic compounds
Heterocyclic compounds with only one n hetero atom and condensed derivatives
Hydrogen Bonding
In Vitro Techniques
Ligands
Male
Mice
Models, Molecular
Molecular Conformation
Organic chemistry
Preparations and properties
Rats
Rats, Sprague-Dawley
Receptors, Opioid, kappa - drug effects
Receptors, Opioid, kappa - metabolism
Stereoisomerism
Structure-Activity Relationship
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Description
Summary:A series of phenyl carboxyl esters 5a-d derived from N-(cyclopropylmethyl)normetazocine was synthesized and evaluated for its selectivity at mu, kappa, and delta opioid receptors. Compound 5a, although 43 times less potent than the reference compound U50488, was specific for kappa receptors, having no detectable affinity for either mu or delta receptors. Greater binding affinity was seen with the diastereoisomer having the 1'R,2'S stereochemistry in the cyclopropyl ring of the nitrogen substituent, which was only 12 times less active than U50488. Antinociceptive activity in the mouse tail flick was only slightly lower than that of U50488 (ED50 = 7.66 vs 4.52 mg/kg). Naloxone fully prevented antinociception induced by (1'R,2'S)-5a at the doses of 2.0 mg/kg. Compound (1'R,2'S)-5a is one of the most kappa-selective non-peptide compounds reported to date. The implications of these results in terms of requirements for kappa ligands are discussed.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00065a009