U‐80816: A novel partial muscarinic agonist

U-80816 (1-(4-(5-methyl-1H-imidazol-1-yl)-2-butynyl)-2-pyrrolidinone is an acetylenic amine which has been investigated as a partial agonist of muscarinic receptors. In vitro U-80816 inhibited binding of (3H)-N-methylscopolamine [(3H)-NMS] and (methyl-3H) oxotremorine-M acetate [3H)-Oxo-M] to the cortical membrance preparation with Ki's of 75 and 3.24 nM, respectively. In the M1 cell line, U-80816 increased phosphatidylinositol (Pl) hydrolysis. However, the maximum increase in the Pl hydrolysis was significantly (P < 0.01) less than oxotremorine and RS 86. Intraperitoneal administration of U-80816 dose-dependently increased striatal acetylcholine (ACh) concentration, and the effect was significant (P < 0.01) at 30 mg/kg. In the presence of hemicholinium-3 (HC-3), U-80816 inhibited the release of (3H)-ACh from hippocampal slices. On the other hand, in the presence of eserine, U-80816 increased the release of (3H)-ACh. In in vivo pharmacological tests, U-80816 produced hypothermia and tremors in mice. This compound failed to produce lacrimation or salivation in mice when administered up to 100 mg/kg. U-80816 antagonized oxotremorine-induced salivation. It is bioavailable to the brain in a significant amount after oral administration and has a sufficiently long duration of action. The in vitro and in vivo pharmacological investigations indicate that U-80816 is a partial agonist of muscarinic receptors.