
Journal of Medicinal Chemistry p. 2138 - 2144 (1994)
Update date:2022-08-05
Topics:
Naylor
Judd
Scopes
Hayes
Birch
The synthesis of 5-(arylacetyl)-4-[(alkylamino)methyl]furo[3,2- c]pyridines (16-23, 26, 27) and their activities as κ-opioid receptor agonists are described. κ-Agonist potency was particularly sensitive to the nature of the basic moiety. In particular, in the rabbit vas deferens (κ- specific tissue), the 3-pyrrolidinol analogue 17 (IC50 = 2.7 nM) was found to be approximately 5-fold more potent than the corresponding pyrrolidine analogue 16 (IC50 = 15 nM). In the rat and hamster vasa deferentia (μ- specific and δ-specific tissues, respectively), 17 showed only weak antagonist activity (pK(B) > 5.5), underlining its selectivity for the κ- opioid receptor. The major activity for 17 is resident in the 4S,3'S-isomer 26 (rabbit vas deferens IC50 = 1.1 nM). Compound 26 displays excellent antinociceptive activity, as determined in the mouse acetylcholine-induced abdominal constriction test (ED50 = 0.001 mg/kg, sc).
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