4-[(Alkylamino)methyl]furo[3,2-c]pyridines: a new series of selective kappa-receptor agonists.
The synthesis of 5-(arylacetyl)-4-[(alkylamino)methyl]furo[3,2-c] pyridines (16-23, 26, 27) and their activities as kappa-opioid receptor agonists are described. kappa-Agonist potency was particularly sensitive to the nature of the basic moiety. In particular, in the rabbit vas deferens (kappa-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 (mu-specific and delta-specific tissues, respectively), 17 showed only weak antagonist activity (pKB > 5.5), underlining its selectivity for the kappa-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).
Department of Medicinal Chemistry, Glaxo Group Research Ltd., Ware, Hertfordshire, England.
A
A
Naylor
D B
DB
Judd
D I
DI
Scopes
A G
AG
Hayes
P J
PJ
Birch
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D006224:Cricetinae; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009294:Narcotics / Q000138:chemical synthesis* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000187:drug effects*; D013237:Stereoisomerism; D014649:Vas Deferens / Q000187:drug effects
D000700:Analgesics; D009294:Narcotics; D011725:Pyridines; D017473:Receptors, Opioid, kappa