HIGHLY SELECTIVE KAPPA-OPIOID ANALGESICS .3. SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF NOVEL N-[2-(1-PYRROLIDINYL)-4-SUBSTITUTED-CYCLOHEXYL]- OR N-[2-(1-PYRROLIDINYL)-5-SUBSTITUTED-CYCLOHEXYL]ARYLACETAMIDE DERIVATIVES

This paper describes the chemical synthesis, µ/ϰ opioid receptor selectivity and analgesic activity of 14 novel N-[2-(l-pyrrolidinyl)-4- or -5-substituted-cyclohexyl]arylacetamide derivatives. The prototype ϰ-selective agonist, PD117302 ((rans-N-methyl-N-[2-(l-pyTTolidinyl)cyclohexyl]benzo[b]thiophene-4-acetamide, 2) has been regio- and stereoselectively substituted in the C-4 and C-5 positions of the cyclohexyl ring with the methyl ether and spiro tetrahydrofuran groups. It is observed that optimal µ/ϰ-receptor selectivity is obtained when the oxygen atom of the methyl ether or the tetrahydrofuran ring is joined to the equatorial C-4 position. Hence, (-)·(5β,7β,8α)-N-methyl-N-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]benzo[6]furan-4-acetamide monohydrochloride (21) has exceptionally high ϰ opioid receptor affinity and selectivity in vitro (ϰ Ki= 0.83 nM, µ/ϰ ratio = 1520) is the most potent ϰ-selective analgesic ever reported. Compound 21 is 25 times more potent than morphine and 17 times more potent than U-62066 (spiradoline, 19) when assayed by the rat paw pressure test by intravenous administration (MPE50= 0.024, 0.6, and 0.4 mg/kg, respectively). © 1990, American Chemical Society. All rights reserved.