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Selective blockade of M 2 and M 3 muscarinic receptors by hexahydrobenzyl‐ fourdapine and a comparison with zamifenacin
Author(s) -
Barlow R.B.,
Bond Susan M.,
Branthwaite A.G.,
Jackson O.,
McQueen D.S.,
Smith Kirsten M.,
Smith Paula J.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb15942.x
Subject(s) - chemistry , muscarinic acetylcholine receptor , carbachol , schild regression , ileum , guinea pig , receptor , stereochemistry , endocrinology , medicine , antagonist , biochemistry , biology
1 4‐Diphenylacetoxy‐N‐ cyclo hexylmethyl‐piperidine HC1 (hexahydro‐benz‐4DAP) is more active as an antagonist of carbachol at receptors in guinea‐pig isolated ileum, log K (pA 2 ) = 6.64±0.14 (s.e. 7 results), than at receptors in guinea‐pig isolated atria, log K = 5.43 ±0.14 (7). In the presence of neostigmine bromide (0.2 μ m ) the value for atria was 5.62 ±0.19 (4), so the lower activity on atria cannot be attributed to hydrolysis of the compound by cholinesterases present in this tissue. 2 The limit of solubility of the free base in Krebs solution (pH 7.6) is about 50 μ m for both hexahydro‐benz‐4DAP and benzyl‐fourdapine (benz‐4DAP). 3 In experiments on guinea‐pig isolated ileum with hexahydro‐benz‐4DAP given together with 4‐DAMP methobromide, the combined dose‐ratio was consistent with competition: similar results were obtained with benz‐4DAP. 4 In rats anaesthetized with pentobarbitone, hexahydro‐benz‐4DAP antagonized the effects of bethanechol on blood‐pressure in doses that had little effect on heart rate or airflow. There was a limit to the effect which could be obtained, however, and the slopes of the Schild plots were less than one. The effects on rat blood‐pressure had a half‐life of at least 30 min. 5 In similar experiments with zamifenacin the slopes of the Schild plots were close to 1 and the compound was 10 to 20 times as active on blood‐pressure at it was on heart‐rate. 6 The limited solubility of the base probably accounts for the flat Schild plots obtained with hexahydro‐benz‐4DAP, which had about 10 fold selectivity for effects on blood‐pressure and was more active than expected from tests on isolated ileum.