U‐80816: A novel partial muscarinic agonist

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Abstract
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.