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The interaction of para fluorohexahydrosiladiphenidol at muscarinic receptors in vitro
Author(s) -
Eglen R.M.,
Michel A.D.,
Montgomery W.W.,
Kunysz E.A.,
Machado C.A.,
Whiting R.L.
Publication year - 1990
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.1476-5381.1990.tb12983.x
Subject(s) - muscarinic acetylcholine receptor , receptor , ileum , endocrinology , medicine , guinea pig , biology , chemistry
1 The antagonistic actions of para fluorohexahydrosiladiphenidol (pFHHSiD) at muscarinic receptors has been studied in cardiac muscle, smooth muscle and cell culture preparations. In this paper, the classification scheme of Doods et al . (1987) is employed. This scheme is based upon differential affinities of muscarinic antagonists. pFHHSiD exhibited high pA 2 values at M 3 receptors mediating contractions of guinea‐pig ileum and oesophageal muscularis mucosae (7.8 and 8.2 respectively) whereas low values were determined at M 2 receptors mediating negative inotropic responses in guinea‐pig atria (6.0). Intermediate pA 2 values were determined at M 1 receptors mediating contractions of the canine femoral and saphenous veins. 2 The pA 2 values of pFHHSiD at receptors mediating endothelial‐dependent relaxation of rat aortic rings, rabbit jugular vein and canine femoral artery (7.6–7.9) were similar to those determined on the ileum. However, the pA 2 values of pFHHSiD at receptors mediating contractions of the guinea‐pig trachea (7.1), which has been previously shown to possess M 3 receptors, were different from those determined in the ileum. 3 The similarity in pA 2 values of pFHHSiD between the M 3 receptors in guinea‐pig ileum and the receptors mediating endothelial‐dependent relaxations provide further evidence for the role of M 3 receptors in this vascular response. Taken together, pA 2 values for pFHHSiD range from 7.1 to 8.2, depending upon the M 3 preparation used. The selectivity of the compound therefore for the M 3 versus the M 2 muscarinic receptor ranged from 13 to 163 fold. 4 At muscarinic receptors mediating stimulation of phosphatidylinositol hydrolysis, pFHHSiD paradoxically displayed a high affinity for the M 1 receptor in the SH‐SY5Y cell line (pA 2 = 7.9) as well as for the M 3 receptor in the human astrocytoma (1321 N1 cell line(pA 2 = 7.6). The value at the M 1 receptor in SH‐SY5Y cells was greater than was observed at M 1 receptors mediating contractions of both the canine saphenous and femoral veins (7.1). 5 pFHHSiD, therefore, clearly delineated M 3 from M 2 muscarinic receptors, whilst the separation between M 1 and M 3 receptors was variable. The reason for the anomalous affinity estimates in some functional studies remains unclear. These data indicate that the pA 2 values for pFHHSiD appear to be tissue‐dependent since the M 3 selectivity varies according to the preparations studied. As a result the utility of pFHHSiD in muscarinic receptor classification is limited.