Document Detail

Probes for narcotic receptor mediated phenomena. 12. cis-(+)-3-Methylfentanyl isothiocyanate, a potent site-directed acylating agent for delta opioid receptors. Synthesis, absolute configuration, and receptor enantioselectivity.
MedLine Citation:
PMID:  3012085     Owner:  NLM     Status:  MEDLINE    
The first enantiomeric pair of irreversible opioid ligands [(+)- and (-)-4] were synthesized in greater than 99.6% optical purity as determined by HPLC analysis of diastereoisomeric derivatives of the intermediate 3-methyl-N-phenyl-4-piperidinamine enantiomers. Single-crystal X-ray analysis of the (R,R)-L-(+)-tartaric acid salt of (-)-9 revealed the absolute configuration to be 3S,4R. The absolute configuration of (-)-3 [cis-(-)-3-methylfentanyl] and (-)-4 derived from (-)-9 is thus 3S,4R and that of (+)-3 and (+)-4 is 3R,4S. The (+) enantiomer of 4 (SUPERFIT) was shown to be highly potent and specific for acylation of delta opioid receptors (to the exclusion of mu) in rat brain membranes like its achiral prototype FIT and was about 10 times as potent as the latter in this assay. The (+)-4 was about 5 times as potent as FIT in acylation of delta receptors in NG108-15 neuroblastoma X glioma hybrid cells and about 50 times as potent as its enantiomer. Both FIT and (+)-4 behaved as partial agonists in inhibition of delta receptor coupled adenylate cyclase in NG108-15 membranes and (+)-4 was 5-10 times more potent than FIT and about 100 times more potent than its enantiomer in this assay. Dibromination of amine 12, catalytic exchange of bromine with tritium gas, and reaction of the labeled amine with thiophosgene afforded [3H]-(+)-4 with a specific activity of 13 Ci/mmol. Previous experiments indicated (+)-4 acylates the same 58 000-dalton glycoprotein previously shown to be acylated by FIT but with less nonspecific labeling. In view of the high potency and specificity of (+)-4 and the availability of its enantiomer, it seems likely that these compounds will prove to be valuable tools for study of the opioid receptor complex.
T R Burke; A E Jacobson; K C Rice; J V Silverton; W F Simonds; R A Streaty; W A Klee
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  29     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1986 Jun 
Date Detail:
Created Date:  1986-07-07     Completed Date:  1986-07-07     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1087-93     Citation Subset:  IM    
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MeSH Terms
Adenylate Cyclase / antagonists & inhibitors
Analgesics / pharmacology
Brain / metabolism
Enkephalin, Methionine / analogs & derivatives,  metabolism
Fentanyl / analogs & derivatives*,  chemical synthesis,  pharmacology
Molecular Conformation
Receptors, Opioid / analysis,  metabolism*
Receptors, Opioid, delta
Receptors, Opioid, mu
Tritium / diagnostic use
X-Ray Diffraction
Reg. No./Substance:
0/Analgesics; 0/Isothiocyanates; 0/Ligands; 0/Receptors, Opioid; 0/Receptors, Opioid, delta; 0/Receptors, Opioid, mu; 10028-17-8/Tritium; 101472-20-2/3-methylfentanyl isothiocyanate; 437-38-7/Fentanyl; 58569-55-4/Enkephalin, Methionine; 61090-95-7/enkephalinamide-Met, Ala(2)-; 85951-63-9/fentanyl isothiocyanate; EC Cyclase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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