SDZ ENS 163 a novel pilocarpine like drug: pharmacological in vitro and in vivo profile.
The thiolactone analogue of pilocarpine, SDZ ENS 163, acts in vitro and in vivo as a partial agonist at M1/M3 and as an antagonist at M2 muscarinic receptors. In vitro, the properties of SDZ ENS 163 have been investigated in several functional models for muscarinic receptors: it is a full agonist at M1 (rat superior cervical ganglion, carbachol = 100%) and a partial agonist at M3 receptors (guinea pig ileum). However, the drug shows antagonistic properties at M2 receptors (rat atria). Radioligand binding studies with 3H-N-methylscopolamine (3H-NMS) using CHO cells expressing m1 or m3 receptors indicate that SDZ ENS 163 does not discriminate between m1 and m3 receptors (Ki 1.5 and 2.4 microM respectively). Regarding phosphoinositide (PI) turnover in A9L cells, SDZ ENS 163 is a partial agonist at m1 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 M1 agonistic and presynaptic M2 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.
Preclinical Research SANDOZ PHARMA Ltd., Basle/Switzerland.
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A
Enz
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Boddeke
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Sauter
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M
Rudin
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G
Shapiro
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D005728:Ganglia, Sympathetic / Q000187:drug effects; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D019832:N-Methylscopolamine; D010276:Parasympatholytics / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D010862:Pilocarpine / Q000031:analogs & derivatives*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D012602:Scopolamine Derivatives / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*
D007093:Imidazoles; D010276:Parasympatholytics; D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D013876:Thiophenes; D010862:Pilocarpine; C075390:SDZ ENS 163; D000109:Acetylcholine; D019832:N-Methylscopolamine