PMID- 10525104
DA - 19991124
DCOM- 19991124
LR - 20011128
IS - 0022-3565
VI - 291
IP - 2
DP - 1999 Nov
TI - Milameline (CI-979/RU35926): a muscarinic receptor agonist with cognition-activating properties: biochemical and in vivo characterization.
PG - 812-22 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 (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.
AD - Parke-Davis Pharmaceutical Research, Division of Warner Lambert Company,
[emd]
FAU - Schwarz, R D
AU - Schwarz RD
FAU - Callahan, M J
AU - Callahan MJ
FAU - Coughenour, L L
AU - Coughenour LL
FAU - Dickerson, M R
AU - Dickerson MR
FAU - Kinsora, J J
AU - Kinsora JJ
FAU - Lipinski, W J
AU - Lipinski WJ
FAU - Raby, C A
AU - Raby CA
FAU - Spencer, C J
AU - Spencer CJ
FAU - Tecle, H
AU - Tecle H
LA - eng
PT - Journal Article
CY - UNITED STATES
TA - J Pharmacol Exp Ther
JID - 0376362
RN - 0 (Cholinesterase Inhibitors)
RN - 0 (Dihydropyridines)
RN - 0 (Muscarinic Agonists)
RN - 0 (Neurotransmitters)
RN - 0 (Oximes)
RN - 0 (Phosphatidylinositols)
RN - 0 (Receptors, Muscarinic)
RN - 139886-32-1 (milameline)
RN - 51-34-3 (Scopolamine)
RN - 51-84-3 (Acetylcholine)
RN - 60-92-4 (Cyclic AMP)
RN - 66428-89-5 (Forskolin)
RN - 7440-09-7 (Potassium)
SB - IM
MH - Acetylcholine/secretion
MH - Animal
MH - Behavior, Animal/*drug effects
MH - Binding Sites
MH - CHO Cells
MH - Cerebral Cortex/*drug effects
MH - Cholinesterase Inhibitors/pharmacology
MH - Cognition/*drug effects
MH - Cyclic AMP
MH - Dihydropyridines/*pharmacology
MH - Dose-Response Relationship, Drug
MH - Electroencephalography/drug effects
MH - Forskolin/metabolism
MH - Hamsters
MH - Human
MH - In Vitro
MH - Macaca mulatta
MH - Male
MH - Muscarinic Agonists/*pharmacology
MH - Neurotransmitters/metabolism
MH - Oximes/*pharmacology
MH - Phosphatidylinositols/metabolism
MH - Potassium/physiology
MH - Rats
MH - Rats, Long-Evans
MH - Receptors, Muscarinic/drug effects
MH - Scopolamine/pharmacology
MH - Support, Non-U.S. Gov't
MH - Time Factors
MH - Transfection
EDAT- 1999/10/19
MHDA- 1999/10/19 00:01
URLF- http://www.jpet.org/cgi/content/full/291/2/812
URLS- http://www.jpet.org/cgi/content/abstract/291/2/812
PST - ppublish
SO - J Pharmacol Exp Ther 1999 Nov;291(2):812-22.