Probes for narcotic receptor mediated phenomena. 15. (3S,4S)-(+)-trans-3-methylfentanyl isothiocyanate, a potent site-directed acylating agent for the delta opioid receptors in vitro.
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.
Kim
C H
CH
Laboratory of Medicinal Chemistry, National Institutes of Health, Bethesda, Maryland 20892.
Rothman
R B
RB
Jacobson
A E
AE
Mattson
M V
MV
Bykov
V
V
Streaty
R A
RA
Klee
W A
WA
George
C
C
Long
J B
JB
Rice
K C
KC
D000215:Acylation; D000067956:Adenylyl Cyclase Inhibitors; D000698:Analgesia; D000818:Animals; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine; D004745:Enkephalins / Q000378:metabolism; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D005910:Glioma / Q000378:metabolism; D006822:Hybrid Cells; D007202:Indicators and Reagents; D008024:Ligands; D008297:Male; D015394:Molecular Structure; D009447:Neuroblastoma / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000067956:Adenylyl Cyclase Inhibitors; D004745:Enkephalins; D007202:Indicators and Reagents; D008024:Ligands; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; C046222:3-methylfentanyl isothiocyanate; C055635:LY 164929; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; D005283:Fentanyl