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J Med Chem. 1991 Aug;34(8):2438-44.

Electrophilic gamma-lactone kappa-opioid receptor probes. Analogues of 2'-hydroxy-2-tetrahydrofurfuryl-5,9-dimethyl-6,7-benzomorphan diastereomers.

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1
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.

Abstract

Benzomorphans with an electrophilic group in the nitrogen substituent were prepared as potentially irreversible ligands for the kappa-opioid receptor. These were synthesized from products of the reaction of normetazocine with the enantiomers of 5-(iodomethyl)-gamma-butyrolactone (11). alpha-Methylene gamma-lactones 5 and 7 and endocyclic alpha,beta-unsaturated gamma-lactones 8 and 9 were prepared from the corresponding saturated gamma-lactones 13 and 23 possessing the "active" (1R,5R,9R)-benzomorphan stereochemistry. Only gamma-lactones 8, 9, 13, and 23, lacking the exocyclic methylene group, retain significant affinities for opioid receptor binding sites when compared with the reference compounds (2"S)-3 and (2"R)-3. As observed with these references compounds, greater binding affinity is also seen with gamma-lactone diastereomers having the 2"S stereochemistry in the nitrogen substituent. Although the gamma-lactones do not bind irreversibly in opioid receptor preparations, they do show kappa-receptor selectivities comparable to those observed for the reference compounds.

PMID:
1652019
DOI:
10.1021/jm00112a019
[Indexed for MEDLINE]

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