Evidence for specific analgesic activity of a muscarinic agonist selected among a new series of acetylenic derivatives

The central and peripheral effects of a series of Oxotremorine/Oxotremorine-M derivatives, previously characterized as muscarinic agonists in isolated preparations, were investigated in in vivo experiments. The molecules were tested for their antinociceptive activity (formalin licking and acetic acid writhing tests) and for their ability to induce tremor in mice. Peripheral cholinergic effects such as salivation, bradycardia, hypotension and intestinal hypermotility were studied in anaesthetized rats. All of the acetylenic compounds acted as muscarinic analgesics displaying the same order of potency shown in in vitro studies. The Oxotremorine-like subset showed a clearer distinction between doses producing antinociception and doses exerting undesirable central/peripheral side effects compared to the Oxotremorine-M derivatives. The most promising profile was displayed by the isoxazolin-3-one Oxotremorine-like derivative (compound 1a), which was characterized by a wider therapeutic window than that of the parent molecule Oxotremorine. Indeed, it produced atropine-sensitive analgesia (ID50 about 0.1 mg/kg i.p.) in the absence of tremorogenic (EC50 2.73 mg/kg i.p.) and cardiovascular effects while lethality occurred only at higher doses (LD50 19 mg/kg i.p.). These results suggest that such a derivative could be a candidate for further development of selective muscarinic analgesics. (C) 2001 Elsevier Science Inc. All rights reserved.