Preclinical and phase 1 clinical characterization of CI-979/RU35926, a novel muscarinic agonist for the treatment of Alzheimer's disease.
In vitro and in vivo characterization in rodents and monkeys shows that CI-979/RU35926 is a partial muscarinic agonist with equal affinity for the five subtypes of muscarinic receptors. It activates central cholinergic receptors as shown by its ability to decrease body temperature, enhance local cortical blood flow and increase cortical arousal measured by QEEG. Further, it reverses spatial memory deficits in rats with ibotenic acid-induced lesions of forebrain cholinergic neurons. Signs of peripheral cholinergic stimulation appear at doses higher or equal to those necessary to produce central activity. In a single-dose tolerance study in young, healthy human volunteers, CI-979/RU35926 was well tolerated at doses of 0.002-1.0 mg with cholinergic symptoms such as hypersalivation and sweating, observed at 2-4 mg. It demonstrated linear pharmacokinetic behavior over a dose range of 0.1 to 4 mg and elimination half-life varied from 2-5 hours. Measurement of unchanged drug in urine suggests that the drug was extensively metabolized. Thus, the safety profile supported further clinical evaluation and CI-979/RU35926 is currently in Phase II clinical trials.
Sedman
A J
AJ
Parke-Davis Pharmaceutical Research, Ann Arbor, MI, 48105, USA.
Bockbrader
H
H
Schwarz
R D
RD
D000293:Adolescent; D000328:Adult; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects; D006224:Cricetinae; D018592:Cross-Over Studies; D003714:Denervation; D004095:Dihydropyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D004311:Double-Blind Method; D004353:Drug Evaluation, Preclinical; D004569:Electroencephalography; D005769:Gastrointestinal Motility / Q000187:drug effects; D006801:Humans; D007051:Ibotenic Acid; D008253:Macaca mulatta; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D010091:Oximes / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism; D013550:Swimming
D004095:Dihydropyridines; D018721:Muscarinic Agonists; D010091:Oximes; D011976:Receptors, Muscarinic; D007051:Ibotenic Acid; C084978:milameline