SDZ ENS 163 a novel pilocarpine like drug: Pharmacological in vitro and in vivo profile

Abstract

The thiolactone analogue of pilocarpine, SDZ ENS 163, acts in vitro and in vivo as a partial agonist at M 1 M 3 and as an antagonist at M 2 muscarinic receptors. In vitro, the properties of SDZ ENZ 163 have been investigated in several functional models for muscarinic receptors: it is full agonist at M 1 (rat, superior cervical ganglion, carbachol = 100%) and a partial agonist at M 3 receptors (guinea pig ileum). However, the drug shows antagonistics properties at M 2 receptors (rat atria). Radiologand binding studies with 3H-N-methylscopolamine ( 3H-NMS) using CHO cells expressing m 1 or m 3 receptors indicate that SDZ ENS 163 does not discriminate between m 1 and m 3 receptors (K i 1.5 and 2.4 μM respectively). Regarding phosphoinositide (PI) turnover in A9L cells, SDZ ENS 163 is a partial agonist at m 1 receptors. In ex vivo neurochemical studies in rats SDZ ENS 163 displays effects characteristic of muscarinic antagonists regarding the turnover of ACh which is increased in the brain. At a similar dose-range SDZ ENS 163 accelerates PI metabolism in the rat brain in vivo and increases the energy of the low frequency band (2–5 Hz) in the rat hippocampal EEG. These effects observed in vivo are consistent with postsynaptic M 1 agonistic and presynaptic M 2 antagonistic activities. Since SDZ ENS 163 at centrally active doses exerts no peripheral cholinergic effects, it may be useful for the symptomatic treatment of Alzheimer's disease.