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

Two subseries of nonquaternized (5a-10a) and quaternized derivatives (5b-10 b) related to oxotremorine and oxotremorine-M were synthesized and tested. The agonist potency at the muscarinic receptor subtypes of the new compound s was estimated in three classical in vitro functional assays: M-1 rabbit v as deferens, M-2 guinea pig left atrium and M-3 guinea pig ileum. In additi on, the occurrence of central muscarinic effects was evaluated as tremorige nic activity after intraperitoneal administration in mice. In in vitro test s a nonselective muscarinic activity was exhibited by all the derivatives w ith potencies values that, in some instances, surpassed those of the refere nce 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-a ntagonist (pD(2)-5.85; pA(2)=4.76, respectively). In in vivo tests nonquate rnary compounds were able to evoke central muscarinic effects, with a poten cy order parallel to that observed in vitro. (C) 1999 Elsevier Science Ltd. All rights reserved.