Synthesis of (1',2'-trans)-3-phenyl-1-[2'-(N-pyrrolidinyl)cyclohexyl]pyrrolid -2-ones as kappa-selective opiates.
(1',2'-trans)-3-Phenyl-1-[2'-(N-pyrrolidinyl)cyclohexyl]pyrrolid-2 -ones (1 and 2) and their 3,4-dichlorophenyl analogues (4 and 5) were synthesized as lactam analogues of U-50,488 (I; a kappa-opiate analgesic developed by Upjohn Company). Compounds 1 and 2 were found to be oxidized by air, in the presence of a strong base, to the 3-hydroxylated derivative 3. Compound 4 gave slightly higher kappa-affinity (Ki = 10 nM) than I, with about half the kappa-selectivity (mu/kappa = 23). Compounds 1 and 3 showed weaker kappa-binding (Ki = 400 nM), with about the same kappa-selectivity as 4. Compound 5, a diastereomer of 4, gave significantly weaker and less selective kappa-binding than 4; likewise, 2 is a weaker and less selective kappa-binder than 1. The binding data of intermediate compounds having the basic skeleton of I seem to reflect the importance of lipophilicity and the detrimental effects of bulky substituents on the amide nitrogen. It is likely that the binding conformation of I at the opiate receptors approaches that of the lactam analogue 4.
Cheng
C Y
CY
School of Pharmacy, College of Medicine, National Taiwan University, Taipei.
Lu
H Y
HY
Lee
F M
FM
Tam
S W
SW
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000818:Animals; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000378:metabolism; D008968:Molecular Conformation; D009294:Narcotics / Q000138:chemical synthesis* / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D013237:Stereoisomerism
D003510:Cyclohexanes; D009294:Narcotics; D011759:Pyrrolidines; D011760:Pyrrolidinones; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer