Milameline (CI-979/RU35926): A muscarinic receptor agonist with cognition-activating properties: Biochemical and in vivo characterization

Milameline (E-1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxaldehyde, O-methy loxime monohydrochloride, CI-979, PD129409, RU35926) was characterized in v itro and evaluated for effects on central and peripheral cholinergic activi ty in rats and rhesus monkeys. In muscarinic binding studies, milameline di splayed nanomolar affinity with an agonist ligand and micromolar affinity w ith antagonist ligands, with approximately equal affinities determined at t he five subtypes of human muscarinic receptors (hM(1)-hM(5)) with whole cel ls or membranes from stably transfected Chinese hamster ovary (CHO) cells. On binding, milameline stimulated phosphatidylinositol hydrolysis in hM(1) and hM(3) CHO cells and inhibited forskolin-activated cAMP accumulation in hM(2) and hM(4) CHO cells. Additionally, it decreased K+-stimulated release of [H-3] acetylcholine from rat cortical slices. Responses were not caused by the inhibition of acetylcholinesterase, and there was no significant bi nding to similar to 30 other neurotransmitter binding sites. In rats, milam eline decreased spontaneous and scopolamine-induced swimming activity, impr oved water-maze performance of animals impaired by basal forebrain lesions, increased cortical blood flow, decreased core body temperature, and increa sed gastrointestinal motility. Electroencephalogram activity in both rats a nd monkeys was characterized by a predominance of low-voltage desynchronize d 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 consi stent with that of a partial muscarinic agonist, with central cholinergic a ctions being produced in rats and monkeys at doses slightly lower than thos e stimulating peripheral cholinergic receptors.