4-[(Alkylamino)methyl]furo[3,2-c]pyridines: A new series of selective κ- receptor agonists

Article abstract of DOI:10.1021/jm00040a004

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).