Electrophilic gamma-lactone kappa-opioid receptor probes. Analogues of 2'-hydroxy-2-tetrahydrofurfuryl-5,9-dimethyl-6,7-benzomorphan diastereomers.
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.
Klein
P
P
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Nelson
W L
WL
D000818:Animals; D001575:Benzomorphans / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D008968:Molecular Conformation; D015394:Molecular Structure; D011957:Receptors, Opioid / Q000378:metabolism*; D017473:Receptors, Opioid, kappa; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001575:Benzomorphans; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; C032478:MR 2034