Telenzepine enantiomers block muscarinic M1-receptors with opposite kinetics.
Stimulation of muscarinic M1-receptors in isolated rabbit vas deferens by McN-A-343 inhibited electrically induced twitch contractions susceptible to competitive blockade by (+)-, (+/-), (-)-telenzepine and pirenzepine (pA2 = 9.12, 8.86, 6.98 and 7.79, respectively). The inhibition of twitch contractions by 10(-6) M McN-A-343 (EC70-80) was reversed by the antimuscarinic agents (at concentrations 10-fold higher than pA2) in a time-dependent manner. The antagonists were then displaced by 3 X 10(-5) M McN-A-343 (30-fold EC70-80), which again led to inhibition of twitch contractions. Assuming first-order kinetics for M1-receptor blockade by the antagonists, t1/2 values for the start and end of blockade were calculated. For (+)-telenzepine, the t1/2 values for the rates for the start and end of blockade were 23 and 174 min, respectively, whereas (-)-telenzepine exhibited an inverse kinetic pattern of 3.0 and 0.38 min, respectively. The extremely slow dissociation of (+)-telenzepine from muscarinic M1-receptors may explain the long-lasting pharmacological effect of this compound in vivo.
Eltze
M
M
Department of Pharmacology, Byk Gulden Pharmaceuticals, Konstanz, F.R.G.
D000818:Animals; D004558:Electric Stimulation; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology*; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013237:Stereoisomerism; D014649:Vas Deferens / Q000187:drug effects
D010276:Parasympatholytics; D011976:Receptors, Muscarinic; C046338:telenzepine; D010890:Pirenzepine