Thiopilocarpine

In contrast to other muscarinic agonists, WAL 2014 FU does not induce bronchospasm in laboratory animals. The present investigation was intended to test the hypothesis that this is due to a particular susceptibility of the drug's effect to antagonism by catecholamines, as a result of partial M3-agonism. The tonic activity of the muscarinic agonists, aceclidine, arecoline, carbachol, McN-A-343, RS 86, thiopilocarpine and WAL 2014 FU, was tested in groups of isolated tracheal muscle of the guinea-pig. Susceptibility to functional antagonism by beta-adrenoceptor stimulation was measured by the displacement of the concentration-force curves by 3 microM noradrenaline. Evaluation of the concentration-force relationship revealed differences in potency and intrinsic activity (carbachol-100%) ranging from 114% for arecoline to 36% for thiopilocarpine (WAL 2014 FU-63%). The catecholamine increased the concentration of agonist which induced 5% of the maximum effect achievable (EC05) values fivefold (carbachol) to more than 4,680 fold (thiopilocarpine) (WAL 2014 FU: 2,860 fold). Regression analysis between the intrinsic activity of the seven compounds and the antagonistic effect of noradrenaline revealed a significant correlation (Spearman correlation coefficient (r[s])=-0.79; p=0.036). Inhibition of the effects of endogenous catecholamines by beta-adrenolysis with 50 microM toliprolol increased the maximal contraction induced by 1 mM WAL 2014 FU, but did not affect maximal contraction induced by 30 microM arecoline. Pretreatment with 0.3-1.0 mM dibutyrylcyclic adenosine monophosphate (DBcAMP) shifted the concentration-response curves of arecoline, WAL 2014 FU and thiopilocarpine in a similar manner to noradrenaline. The results exclude an important contribution of adenylate cyclase-coupled M2-receptors to the susceptibility of tracheal contraction by muscarinic agonists to functional antagonism by noradrenaline, but emphasize the importance of intrinsic activity at the M3-receptors. The pronounced susceptibility of WAL 2014 FU-induced contraction to functional antagonism by beta-adrenoceptor activation provides an explanation for the failure of the drug to induce bronchospasm in vivo.

Scopolamine-induced cognitive impairment was used in healthy men to evaluate the central nervous system activity of the new cholinomimetic SDZ ENS-163. Eighteen subjects were treated in a crossover design with oral placebo/intravenous saline, 50 mg of oral SDZ ENS-163/intravenous saline, oral placebo/0.4 mg of intravenous scopolamine, and 50 mg of oral SDZ ENS-163/0.4 mg of intravenous scopolamine. The administration of placebo with scopolamine caused significant cognitive impairment, as assessed by the Computerized Neuropsychological Test Battery (CNTB), and also decreased salivation and heart rate. In contrast, SDZ ENS-163 with saline had no effect on CNTB scores, increased salivation, and increased heart rate. Despite the observed cholinomimetic effects of SDZ ENS-163 when administered with saline, the changes in CNTB scores, heart rate, and salivation were indistinguishable between placebo/scopolamine and SDZ ENS-163/scopolamine. Thus, 50 mg of oral SDZ ENS-163 has cholinomimetic activity in normal men, but this dose is insufficient to reverse the muscarinic effects of 0.4 mg of intravenous scopolamine.