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.