SELECTIVE REVERSIBLE AND IRREVERSIBLE LIGANDS FOR THE KAPPA-OPIOID RECEPTOR

(+/-)-(5-beta,7-alpha,8-beta)-3,4-Dichloro-N-methyl-N-[3-methylene-2-oxo-8-L(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-7-yl]benzeneacetamide (14) and its (5-alpha,7-alpha,8-beta) diastereomer 15 have been synthesized from 1,4-cyclohexanedione monoethylene ketal (1) in 10 steps. Compound 14, which we have designated SMBU-1, was found to bind with moderate affinity (K(i) = 109 nM) and good selectivity (mu/kappa = 29) to the kappa-opioid receptor, while 15 was only 1/10 as potent as a kappa-ligand. Preincubation of brain membranes with 14 resulted in wash-resistant inhibition of kappa-receptor binding (69 +/- 6% of control at 10(-6) M). The ketone precursor trans-N-methyl-N-[5-oxo-2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (12) showed a higher kappa-affinity (K(i) = 78 nM) and a much higher kappa-selectivity (mu/kappa = 166) than 14. Compound 10, the ethylene ketal precursor of 12, exhibited a similar receptor binding profile to 14, with increased kappa-selectivity (mu/kappa = 55), while ketal 11, being a regioisomer of 10 and an oxygen isostere of the kappa-selective analgesic spiradoline (U-62,066), demonstrated the highest kappa-affinity (K(i) = 1.5 nM) and kappa-selectivity (mu/kappa = 468) observed in this series.