Isothiocyanate-Substituted .kappa.-Selective Opioid Receptor Ligands Derived from N-Methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]phenylacetamide

The synthesis of isothiocyanate-substituted kappa-selective opioid ligands derived from N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]ethyl]phenylacetami de (8) and their effects in radioligand displacement assays are reported. Ligands 3-5 with the S-absolute configuration were prepared with the...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1994-09, Vol.37 (18), p.2856-2864
Main Authors: Weerawarna, S. Ananda, Davis, Ronda D, Nelson, Wendel L
Format: Article
Language:English
Subjects:
Acetamides - chemical synthesis
Acetamides - metabolism
Acetanilides - chemistry
Animals
Binding, Competitive
Brain - metabolism
Guinea Pigs
In Vitro Techniques
Isothiocyanates - chemical synthesis
Isothiocyanates - metabolism
Radioligand Assay
Receptors, Opioid, kappa - metabolism
Stereoisomerism
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Summary:The synthesis of isothiocyanate-substituted kappa-selective opioid ligands derived from N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]ethyl]phenylacetami de (8) and their effects in radioligand displacement assays are reported. Ligands 3-5 with the S-absolute configuration were prepared with the isothiocyanate functionality at the 2-, 3-, and 4-positions in the phenylacetamide aromatic ring. The 2-isothiocyanato-4,5-dichlorophenylacetamide 6 was prepared to evaluate the effect of 4,5-dichloro substitution in the same aromatic ring as the 2-isothiocyanate function. N-Methyl-N-[(1S)-1-(4-isothiocyanatophenyl)-2-(1-pyrrolidinyl) ethyl]-3,4-dichlorophenylacetamide (7), with the 4-isothiocyanate function in the 1-phenyl ring, was prepared for comparison with the other compounds in the series. Of the prepared ligands, 7 and 8 (IC50s congruent to 1.4-1.8 nM) were approximately equal in affinity with 2 (ICI-199,441), followed by 3 and 6. All of these compounds were more kappa-selective than 2, as well. The binding characteristics of 8 show that the previously reported 4,5-dichloro substitution is not required for high affinity and kappa-selectivity. All of the synthesized isothiocyanate-substituted ligands irreversibly inhibited radioligand binding to guinea pig brain membrane preparations, including compound 2 (ICI-199,441) which had no isothiocyanate functionality.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00044a006