Pharmacodynamic profile of the M1 agonist talsaclidine in animals and man.
In functional pharmacological assays, talsaclidine has been described as a functionally preferential M1 agonist with full intrinsic activity, and less pronounced effects at M2- and M3 receptors. In accordance with this, cholinomimetic central activation measured in rabbits by EEG recordings occurred at a 10 fold lower dose than that inducing predominantly M3-mediated side effects. This pharmacological profile is also reflected in the clinical situation: Both in healthy volunteers and in Alzheimer patients--unlike after unspecific receptor stimulation through cholinesterase inhibitors--the mainly M3-mediated gastrointestinal effects (like nausea and vomiting) were not dose-limiting. Rather, sweating and hypersalivation, mediated through muscarinic receptors, occurred dose-dependently and were finally dose-limiting. In contrast to talsaclidine, sabcomeline had a less pronounced functional M1 selectivity in pharmacological assays. This was also shown in anaesthetized guinea pigs where sabcomeline alone induced bronchoconstriction, and in the rabbit EEG where central activation and cholinergic side effects occurred in the same dose range. Neither drug, however, showed convincing improvement of cognitive functions in patients with mild-to-moderate Alzheimer's disease. This asks for a reassessment of the muscarinic hypothesis for the treatment of this disease.
Wienrich
M
M
International Project Management, Boehringer Ingelheim GmbH, Germany. wienrich@ing.boehringer-ingelheim.com
Meier
D
D
Ensinger
H A
HA
Gaida
W
W
Raschig
A
A
Walland
A
A
Hammer
R
R
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000328:Adult; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001986:Bronchial Spasm / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006801:Humans; D007097:Imines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D009130:Muscle, Smooth / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology; D011812:Quinuclidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D007097:Imines; D018721:Muscarinic Agonists; D011412:Propanolamines; D011812:Quinuclidines; D011976:Receptors, Muscarinic; C079885:talsaclidine fumarate; C073327:toliprolol; C109640:sabcomeline