Selective Reversible and Irreversible Ligands for the k Opioid Receptor
Journal
Journal of Medicinal Chemistry
Journal Volume
35
Journal Issue
12
Pages
2243-2247
Date Issued
1992
Author(s)
Abstract
(±)-(5β,7α,8β)-3,4-Dicchloro-N-methyl-N-[3-methylene-2-oxo-8-(1-pyrrolidmyl)-1-oxaspiro[4,5]dec-7-yl]benzeneacetamide (14) and its (5α,7α,8β) 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 (Ki = 109 nM) and good selectivity (μ/k = 29) to the k opioid receptor, while 15 was only 1/10 as potent as a k ligand. Preincubation of brain membranes with 14 resulted in wash-resistant inhibition of -receptor binding (69 ± 6% of control at 10-6 M). The ketone precursor irans-N-methyl-N-[5-oxo-2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (12) showed a higher -affinity (Ki = 78 nM) and a much higher -selectivity (μ/k = 166) than 14. Compound 10, the ethylene ketal precursor of 12, exhibited a similar receptor binding profile to 14, with increased k-selectivity (μ/k - 55), while ketal 11, being a regioisomer of 10 and an oxygen isostere of the k-selective analgesic spiradoline (U-62,066), demonstrated the highest k-affínity (Ki= 1.5 nM) and -selectivity (μ/k = 468) observed in this series. © 1992, American Chemical Society. All rights reserved.
Type
journal article