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 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.
Weerawarna
S A
SA
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Davis
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RD
Nelson
W L
WL
D000081:Acetamides / Q000138:chemical synthesis* / Q000378:metabolism; D000083:Acetanilides / Q000737:chemistry*; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D017879:Isothiocyanates / Q000138:chemical synthesis / Q000378:metabolism; D011869:Radioligand Assay; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D013237:Stereoisomerism
D000081:Acetamides; D000083:Acetanilides; D017879:Isothiocyanates; D017473:Receptors, Opioid, kappa; C089009:N-methyl-N-(1-phenyl-2-(1-pyrrolidinyl)ethyl)phenylacetamide