SDZ ENS 163 is a selective M1 agonist and induces release of acetylcholine

Summary 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 mol/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 mol/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.Send offprint requests to H. W. G. M. Boddeke at the above address