Abstract:
:Recently we reported the synthesis of the first enantiomeric pair of irreversible opioid ligands [(3S,4R)-(-)- and (3R,4S)-(+)-cis-4, SUPERFIT] and specific interaction of the latter with the delta receptor. Here we report another enantiomeric pair of irreversible opioid ligands, (+)-trans- and (-)-trans-3-methylfentanyl isothiocyanates [(3S,4S)-(+)-trans- and (3R,4R)-(-)-trans-4]. A single-crystal X-ray analysis of the 2,4,6-trinitrobenzenesulfonic acid salt of (+)-trans-3-methyl-N-phenyl-4-piperidinamine [(+)-trans-8] revealed it (and, therefore, 4) to have the trans configuration and the absolute configuration of (+)-trans-8 to be 3S,4S. The (+)-trans enantiomer of 4 was shown to be highly potent and about 10-fold more selective as an acylating agent than (-)-trans-4 for the higher affinity [3H]DADL (delta) binding site in rat brain membranes. In that assay, (+)-trans-4 and (+)-cis-4 were essentially equipotent as affinity ligands, and the levo enantiomers were considerably less potent. (+)-trans-4 was, thus, a potent, subtype-selective acylating agent for the delta opioid receptor in vitro. With membranes from NG108-15 neuroblastoma x glioma hybrid cells, containing only delta receptors, (+)-cis-4 was found to be a little more potent than (+)-trans-4. Similarly, (+)-cis-4 is the most effective inhibitor of adenylate cyclase in these membranes, (+)-trans-4 has weak activity, and the levo enantiomers are inactive. Only (+)-cis-4 was found to have antinociceptive activity in vivo.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Kim CH,Rothman RB,Jacobson AE,Mattson MV,Bykov V,Streaty RA,Klee WA,George C,Long JB,Rice KCdoi
10.1021/jm00126a040subject
Has Abstractpub_date
1989-06-01 00:00:00pages
1392-8issue
6eissn
0022-2623issn
1520-4804journal_volume
32pub_type
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