NEUROCHEMICAL EFFECTS OF THE M(1) MUSCARINIC AGONIST XANOMELINE (LY246708 NNC11-0232)/

Xanomeline diazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine)] was eval uated in vivo in rat brain for effects on neurotransmitter turnover an d inhibition of ex vivo binding of muscarinic radioligands. Xanomeline produced dose-related increases in the metabolite of dopamine, dihydr oxyphenylacetic acid (DOPAC), in striatum. The increases in striatal D OPAC levels produced by xanomeline were antagonized by the relatively selective M(1) antagonist trihexyphenidyl, suggesting that xanomeline interacts with M(1) heteroreceptors on dopamine nerve terminals. Xanom eline produced small increases in striatal acetylcholine levels and di d not antagonize the large increases in acetylcholine produced by the nonselective muscarinic agonist oxotremorine, indicating that xanomeli ne did not block M(2) autoreceptors. Xanomeline inhibited ex vivo bind ing of muscarinic radioligands to homogenates of brain and the inhibit ion of ex vivo binding occurred in the same dose range as increases in DOPAC levels. Xanomeline did not appreciably induce salivation or ant agonize oxotremorine-induced salivation indicating that xanomeline doe s not interact with M(3) receptors. The effects of xanomeline on ex vi vo binding and DOPAC levels lasted for about 3 hr and were evident aft er oral administration. An analog of xanomeline with similar in vivo e ffects did not inhibit acetylcholinesterase or choline acetyltransfera se and inhibited choline uptake only at concentrations much higher tha n those required to inhibit binding. These data indicate xanomeline is selective agonist for M(1) over M(2) and M(3) receptors in vivo in ra t. It is not known whether xanomeline interacts with m(4) or m(5) rece ptors in vivo.