title: SDZ ENS 163 is a selective M1 agonist and induces release of acetylcholine.
abstract: In the present study some pharmacological properties of the new muscarinic agonist SDZ ENS 163; (+)-(3S,cis)-3-ethyldihydro-4-[(1-methyl-1H-imidazol-5-yl) methyl-2(3H)-thiophenonedihydrogenphosphate] have been investigated. In the rat superior cervical ganglion, a model for M1 muscarinic receptors, SDZ ENS 163 induced concentration-dependent depolarizations (pD2 = 6.5 +/- 0.3; efficacy = 128 +/- 4.2% compared to carbachol). SDZ ENS 163 was a very weak partial agonist with respect to M2 receptor-induced decrease in contractile force in rat left atria (efficacy = 14 +/- 2.9%). In addition, SDZ ENS 163 competitively antagonized the effect of carbachol in rat left atria (pA2 = 5.8 +/- 0.2). In the guinea-pig ileum SDZ ENS 163 was a partial agonist with respect to force of contraction mediated by M3 receptors (pD2 = 5.3 +/- 0.1; efficacy = 72 +/- 4.2%). The oxotremorine-induced inhibition of the electrically stimulated release of acetylcholine (ACh) in rat hippocampal slices was reversed by SDZ ENS 163 (pA2 = 5.5 +/- 0.1). In addition after oral administration SDZ ENS 163 (3-10 mumol/kg) reduced brain ACh levels, which is indicative of increased ACh turnover. Finally, increases in energy of the low frequency band (2-5 Hz) were observed in rat hippocampal EEG after intraperitoneal administration of SDZ ENS 163 (0.3-30 mumol/kg). We conclude that SDZ ENS 163 is a selective M1 agonist in vitro with an additional M2 antagonistic effect. The in vivo effects of SDZ ENS 163 may result both from postsynaptic M1 agonistic as well as M2 receptor antagonistic activity. The unique pharmacological profile of SDZ ENS 163 may prove clinically favourable for treatment of cognitive deficits.
authors.affiliation: Sandoz Pharma Ltd, Preclinical Research, Basle, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Enz
authors.forename: G
authors.initials: G
authors.lastname: Shapiro
authors.forename: P
authors.initials: P
authors.lastname: Supavilai
authors.forename: H W
authors.initials: HW
authors.lastname: Boddeke
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D003864:Depression, Chemical; D004558:Electric Stimulation; D004569:Electroencephalography / Q000187:drug effects; D005727:Ganglia, Spinal / Q000187:drug effects; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000648:ultrastructure; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D007082:Ileum / Q000187:drug effects / Q000648:ultrastructure; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000502:physiology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D007093:Imidazoles; D011976:Receptors, Muscarinic; D013876:Thiophenes; C075390:SDZ ENS 163; D000109:Acetylcholine