piperidines and hexocyclium

The role of four muscarinic receptor subtypes M1, M2, M3 and M4 which have been characterized pharmacologically was examined in motility control of isolated rat gastric fundus. Acetylcholine produced concentration-dependent tonic contraction of isolated rat fundus (EC50 = 9.64 +/- 0.14 x 10(-8)M). These contractions were concentration-dependently antagonized by atropine (KB = 2.45 x 10(-11)M), M1 selective blockers telenzepine (KB = 6.64 x 10(-11)M) and pirenzepine (KB = 2.3 x 10(-8)M), and hexocyclium (KB = 2.82 x 10(-10)M). M3-selective blocker p-fluoro-hexahydro-sila-difenidol (pFHHSiD) was a less potent antagonist (KB = 2.3 x 10(-8)M), while M2 and M4-selective methoctramine produced only weak blockade of tonic contractions caused by acetylcholine (KB = 4.68 x 10(-6)M). These results suggest that only M1 and M3 muscarinic receptors have functional roles in motility control of rat gastric fundus, M1 receptors being more important.

Topics: Acetylcholine; Animals; Atropine; Diamines; Female; Gastric Fundus; Gastrointestinal Motility; Male; Muscarinic Antagonists; Piperazines; Piperidines; Pirenzepine; Rats; Rats, Wistar; Receptors, Muscarinic

1. In an attempt to assess the structural requirements for the muscarinic receptor selectivity of hexahydro-diphenidol (hexahydro-difenidol) and hexahydro-sila-diphenidol (hexahydro-sila-difenidol), a series of structurally related C/Si pairs were investigated, along with atropine, pirenzepine and methoctramine, for their binding affinities in NB-OK 1 cells as well as in rat heart and pancreas. 2. The action of these antagonists at muscarinic receptors mediating negative inotropic responses in guinea-pig atria and ileal contractions has also been assessed. 3. Antagonist binding data indicated that NB-OK 1 cells (M1 type) as well as rat heart (cardiac type) and pancreas (glandular/smooth muscle type) possess different muscarinic receptor subtypes. 4. A highly significant correlation was found between the binding affinities of the antagonists to muscarinic receptors in rat heart and pancreas, respectively, and the affinities to muscarinic receptors in guinea-pig atria and ileum. This implies that the muscarinic binding sites in rat heart and the receptors in guinea-pig atria are essentially similar, but different from those in pancreas and ileum. 5. The antimuscarinic potency of hexahydro-diphenidol and hexahydro-sila-diphenidol at the three subtypes was influenced differently by structural modifications (e.g. quaternization). Different selectivity profiles for the antagonists were obtained, which makes these compounds useful tools to investigate further muscarinic receptor heterogeneity. Indeed, the tertiary analogues hexahydro-diphenidol (HHD) and hexahydro-sila-diphenidol (HHSiD) had an M1 = glandular/smooth muscle greater than cardiac selectivity profile, whereas the quaternary analogues HHD methiodide and HHSiD methiodide were M1 preferring (M1 greater than glandular/smooth muscle, cardiac).

Topics: Animals; Cells, Cultured; Guinea Pigs; Humans; Ileum; In Vitro Techniques; Male; Muscle, Smooth; Myocardium; Pancreas; Parasympatholytics; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, Muscarinic; Stereoisomerism; Structure-Activity Relationship

The present study was designed to further characterize the presynaptic muscarinic M1-receptor responsible for the inhibition of neurogenic contractions in the isolated rabbit vas deferens. Electrically induced twitch contractions of this preparation were inhibited by the M1-agonist, McN-A-343, and by some of its analogs: 4-chloro-phenyl derivative greater than McN-A-343 greater than trans-olefinic analog greater than cis-olefinic analog. The same rank order of potency was observed for these agonists to raise the blood pressure of pithed rats by stimulation of M1-receptors in sympathetic ganglia. A highly significant correlation was found between the antimuscarinic potencies of atropine, pirenzepine and a series of 9 antagonists structurally related to the ganglionic M1 beta-receptor selective compounds, hexocyclium and hexahydro-difenidol, to antagonize the McN-A-343-induced inhibition of twitch contractions in rabbit vas deferens or the muscarine-induced depolarization in rat isolated superior cervical ganglia. It is suggested that the presynaptic muscarinic receptor that mediates inhibition of neurogenic contractions in rabbit vas deferens is of the ganglionic M1 beta-type.

Topics: (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; Animals; Atropine; Binding Sites; Blood Pressure; Electric Stimulation; Ganglia, Sympathetic; Male; Muscle Contraction; Piperazines; Piperidines; Pirenzepine; Rabbits; Rats; Rats, Inbred Strains; Receptors, Muscarinic; Receptors, Neurotransmitter; Vas Deferens