The interaction of parafluorohexahydrosiladiphenidol at muscarinic receptors in vitro.
1. The antagonistic actions of parafluorohexahydrosiladiphenidol (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 pA2 values at M3 receptors mediating contractions of guinea-pig ileum and oesophageal muscularis mucosae (7.8 and 8.2 respectively) whereas low values were determined at M2 receptors mediating negative inotropic responses in guinea-pig atria (6.0). Intermediate pA2 values were determined at M1 receptors mediating contractions of the canine femoral and saphenous veins. 2. The pA2 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 pA2 values of pFHHSiD at receptors mediating contractions of the guinea-pig trachea (7.1), which has been previously shown to possess M3 receptors, were different from those determined in the ileum. 3. The similarity in pA2 values of pFHHSiD between the M3 receptors in guinea-pig ileum and the receptors mediating endothelial-dependent relaxations provide further evidence for the role of M3 receptors in this vascular response. Taken together, pA2 values for pFHHSiD range from 7.1 to 8.2, depending upon the M3 preparation used. The selectivity of the compound therefore for the M3 versus the M2 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 M1 receptor in the SH-SY5Y cell line (pA2 = 7.9) as well as for the M3 receptor in the human astrocytoma (1321 NI cell line (pA2 = 7.6). The value at the M1 receptor in SH-SY5Y cells was greater than was observed at M1 receptors mediating contractions of both the canine saphenous and femoral veins (7.1). 5. pFHHSiD, therefore, clearly delineated M3 from M2 muscarinic receptors, whilst the separation between M1 and M3 receptors was variable. The reason for the anomalous affinity estimates in some functional studies remains unclear. These data indicate that the pA2 values for pFHHSiD appear to be tissue-dependent since the M3 selectivity varies according to the preparations studied. As a result the utility of pFHHSiD in muscarinic receptor classification is limited.
Eglen
R M
RM
Institute of Pharmacology, Syntex Research, Palo Alto, CA 94304.
Michel
A D
AD
Montgomery
W W
WW
Kunysz
E A
EA
Machado
C A
CA
Whiting
R L
RL
D000818:Animals; D001254:Astrocytoma / Q000378:metabolism; D002478:Cells, Cultured; D004285:Dogs; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007537:Isometric Contraction; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects*
D010276:Parasympatholytics; D010716:Phosphatidylinositols; D010880:Piperidines; D011976:Receptors, Muscarinic; C058297:4-fluorohexahydrosiladifenidol