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

Bioorg Med Chem. 1999 Aug;7(8):1539-47. doi: 10.1016/s0968-0896(99)00107-8.

Abstract

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: M1 rabbit vas deferens, M2 guinea pig left atrium and M3 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 M3-agonist/M1-antagonist (pD2 = 5.85; pA2 = 4.76, respectively). In in vivo tests non-quaternary compounds were able to evoke central muscarinic effects, with a potency order parallel to that observed in vitro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrial Function
  • Cholinergic Agents / chemical synthesis
  • Cholinergic Agents / pharmacology
  • Guinea Pigs
  • Heart Atria / drug effects
  • Ileum / drug effects
  • Ileum / physiology
  • In Vitro Techniques
  • Magnetic Resonance Spectroscopy
  • Male
  • Mice
  • Muscle Contraction / drug effects
  • Oxotremorine / analogs & derivatives*
  • Oxotremorine / chemical synthesis
  • Oxotremorine / pharmacology
  • Rabbits
  • Receptors, Muscarinic / drug effects*
  • Structure-Activity Relationship
  • Tremor / chemically induced
  • Vas Deferens / drug effects
  • Vas Deferens / physiology

Substances

  • Cholinergic Agents
  • Receptors, Muscarinic
  • Oxotremorine