In vitro and in vivo evaluation of the subtype-selective muscarinic agonist PD 151832.
PD 151832 is a potent partial muscarinic agonist that displays a high level of functional selectivity for the muscarinic m1 receptor subtype, as evidenced by its selective stimulation of PI turnover and cellular metabolic activity in transfected Hm1-CHO cells at concentrations that produce minimal stimulation of other cloned human muscarinic receptors. PD 151832 enhanced the amplification of Hm1-transfected NIH-3T3 cells at concentrations lower than those required to produce similar effects in Hm2 or Hm3-transfected cells. The functional m1 selectivity of PD 151832 is consistent with its improvement of mouse water maze performance at doses far lower than those required to produce peripheral parasympathetic side effects.
Jaen
J
J
Department of Chemistry, Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan 48105, USA.
Barrett
S
S
Brann
M
M
Callahan
M
M
Davis
R
R
Doyle
P
P
Eubanks
D
D
Lauffer
D
D
Lauffer
L
L
Lipinski
W
W
D016475:3T3 Cells / Q000378:metabolism; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D005746:Gastric Emptying / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018721:Muscarinic Agonists / Q000145:classification / Q000378:metabolism / Q000494:pharmacology*; D010091:Oximes / Q000378:metabolism / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection
D019086:Bridged Bicyclo Compounds, Heterocyclic; D018721:Muscarinic Agonists; D010091:Oximes; C118323:PD 151832; D010716:Phosphatidylinositols; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic