Interaction of p-F-HHSiD (p-Fluoro-hexahydrosila-difenidol) at muscarinic receptors in guinea-pig trachea.
1. para-Fluoro-hexahydrosila-difenidol (p-F-HHSiD) has been proposed as an M3 selective antagonist. However, the M3 selectivity is variable in that it exhibits a high pA2 value for M3 muscarinic receptors in guinea-pig ileum but a low value at muscarinic receptors in guinea-pig trachea. 2. The pA2 value in the trachea was found to be agonist independent since similar pA2 values were found when acetylcholine, carbachol, (+)-cis-dioxolane or OXA-22 were used (7.13, 7.03, 6.85 and 6.97, respectively). The pA2 value was not meaningfully increased when the equilibrium period was increased from 60 to 180 min. The pA2 value was unaffected by blockade of M1 or M2 receptors, using 0.1 microM pirenzepine or methoctramine (7.03 and 7.14, respectively). p-F-HHSiD and atropine appeared to act at the same site, as adjudged by combination concentration-ratio studies. 3. The pA2 values for p-F-HHSiD vary by 10 fold between ileal (8.0) and tracheal M3 receptors (7.0). The precise reason for this is unknown, but appears to be unrelated to conditions of disequilibrium that could be detected. The antagonist should therefore only be employed to distinguish M3 or M1 from M2 receptors. In this respect, although the M1/M3 vs M2 discrimination is relatively large (68 fold), p-F-HHSiD exhibits similar properties to other putative M3 selective antagonists such as 4-diphenylacetoxy-N-methyl piperidine methiodide (4-DAMP) or the parent compound, hexahydrosiladifenidol (HHSiD).
Eglen
R M
RM
Institute of Pharmacology, Syntex Research, Palo Alto, CA 94304.
Cornett
C M
CM
Whiting
R L
RL
D000818:Animals; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007537:Isometric Contraction; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D010276:Parasympatholytics / Q000494:pharmacology*; D010277:Parasympathomimetics / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects*; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
D010276:Parasympatholytics; D010277:Parasympathomimetics; D010880:Piperidines; D011976:Receptors, Muscarinic; C058297:4-fluorohexahydrosiladifenidol