Synthesis and functional characterization of novel derivatives related to oxotremorine and oxotremorine-M

Two subseries of nonquaternized (5a-10a) and quaternized derivatives (5b-10b) related to oxotremorine and oxotremorine-M were synthesized and tested. The agonist potency at the muscarinic receptor subtypes of the new compounds was estimated in three classical in vitro functional assays: M-1 rabbit vas deferens, M-2 guinea pig left atrium and M-3 guinea pig ileum. In addition, the occurrence of central muscarinic effects was evaluated as tremorigenic activity after intraperitoneal administration in mice. In in vitro tests a nonselective muscarinic activity was exhibited by all the derivatives with potencies values that, in some instances, surpassed those of the reference compounds (i.e. 8b). Functional selectivity was evidenced only for the oxotremorine-like derivative 9a, which behaved as a mixed M-3-agonist/M-1-antagonist (pD(2)-5.85; pA(2)=4.76, respectively). In in vivo tests nonquaternary compounds were able to evoke central muscarinic effects, with a potency order parallel to that observed in vitro. (C) 1999 Elsevier Science Ltd. All rights reserved.