RT Journal Article SR Electronic T1 Milameline (CI-979/RU35926): A Muscarinic Receptor Agonist with Cognition-Activating Properties: Biochemical and In Vivo Characterization JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 812 OP 822 VO 291 IS 2 A1 Roy D. Schwarz A1 Michael J. Callahan A1 Linda L. Coughenour A1 Melvin R. Dickerson A1 Jack J. Kinsora A1 William J. Lipinski A1 Charlotte A. Raby A1 Carolyn J. Spencer A1 Haile Tecle YR 1999 UL http://jpet.aspetjournals.org/content/291/2/812.abstract AB Milameline (E-1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxaldehyde,O-methyloxime monohydrochloride, CI-979, PD129409, RU35926) was characterized in vitro and evaluated for effects on central and peripheral cholinergic activity in rats and rhesus monkeys. In muscarinic binding studies, milameline displayed nanomolar affinity with an agonist ligand and micromolar affinity with antagonist ligands, with approximately equal affinities determined at the five subtypes of human muscarinic receptors (hM1–hM5) with whole cells or membranes from stably transfected Chinese hamster ovary (CHO) cells. On binding, milameline stimulated phosphatidylinositol hydrolysis in hM1 and hM3 CHO cells and inhibited forskolin-activated cAMP accumulation in hM2 and hM4 CHO cells. Additionally, it decreased K+-stimulated release of [3H]acetylcholine from rat cortical slices. Responses were not caused by the inhibition of acetylcholinesterase, and there was no significant binding to ∼30 other neurotransmitter binding sites. In rats, milameline decreased spontaneous and scopolamine-induced swimming activity, improved water-maze performance of animals impaired by basal forebrain lesions, increased cortical blood flow, decreased core body temperature, and increased gastrointestinal motility. Electroencephalogram activity in both rats and monkeys was characterized by a predominance of low-voltage desynchronized activity consistent with an increase in arousal. Milameline also reversed a scopolamine-induced impairment of attention on a continuous-performance task in monkeys. Thus, milameline possesses a pharmacological profile consistent with that of a partial muscarinic agonist, with central cholinergic actions being produced in rats and monkeys at doses slightly lower than those stimulating peripheral cholinergic receptors. The American Society for Pharmacology and Experimental Therapeutics