title: Milameline (CI-979/RU35926): a muscarinic receptor agonist with cognition-activating properties: biochemical and in vivo characterization.
abstract: 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 (hM(1)-hM(5)) with whole cells 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 [(3)H]acetylcholine from rat cortical slices. Responses were not caused by the inhibition of acetylcholinesterase, and there was no significant binding to approximately 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.
authors.affiliation: Parke-Davis Pharmaceutical Research, Division of Warner Lambert Company, Ann Arbor, Michigan, USA. roy.schwarz@wl.com
authors.forename: R D
authors.initials: RD
authors.lastname: Schwarz
authors.forename: M J
authors.initials: MJ
authors.lastname: Callahan
authors.forename: L L
authors.initials: LL
authors.lastname: Coughenour
authors.forename: M R
authors.initials: MR
authors.lastname: Dickerson
authors.forename: J J
authors.initials: JJ
authors.lastname: Kinsora
authors.forename: W J
authors.initials: WJ
authors.lastname: Lipinski
authors.forename: C A
authors.initials: CA
authors.lastname: Raby
authors.forename: C J
authors.initials: CJ
authors.lastname: Spencer
authors.forename: H
authors.initials: H
authors.lastname: Tecle
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001665:Binding Sites; D016466:CHO Cells; D002540:Cerebral Cortex / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects*; D005576:Colforsin / Q000378:metabolism; D006224:Cricetinae; D000242:Cyclic AMP; D004095:Dihydropyridines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008253:Macaca mulatta; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D011188:Potassium / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D011976:Receptors, Muscarinic / Q000187:drug effects; D012601:Scopolamine / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
chemical_list: D002800:Cholinesterase Inhibitors; D004095:Dihydropyridines; D018721:Muscarinic Agonists; D018377:Neurotransmitter Agents; D010091:Oximes; D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; D005576:Colforsin; D012601:Scopolamine; D000242:Cyclic AMP; D000109:Acetylcholine; C084978:milameline; D011188:Potassium