Highly selective .kappa.-opioid analgesics. 3. Synthesis and structure-activity relationships of novel N-[2-(1-pyrrolidinyl)-4- or -5-substituted cyclohexyl]arylacetamide derivatives

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Abstract
This paper describes the chemical synthesis, .mu./.kappa. opioid receptor selectivity and analgesic activity of 14 novel N-[2-(1-pyrrolidinyl)-4- or -5-substituted-cyclohexyl]arylacetamide derivatives. The prototype .kappa.-selective agonist, PD117302 (trans-N-methyl-N-[2-(1-pyrrolidinyl)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 .mu./.kappa.-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, (-)-(5.beta.,7.beta.,8.alpha.)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzo[b]furan-4-acetamide monohydrochloride (21) has exceptionally high .kappa. opioid receptor affinity and selectivity in vitro (.kappa. Ki = 0.83 nM, .mu./.kappa. ratio = 1520) is the most potent .kappa.-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).