Disease relevance of hexahydrosiladifenidol

• 3. Hexahydrosiladifenidol (HHSiD), an ileal-selective competitive muscarinic antagonist, was about as effective an antagonist as the clinically useful drugs oxybutynin or dicyclomine, both in vitro and in vivo, suggesting that HHSiD may have useful therapeutic effects for the treatment of urinary incontinence [1].

High impact information on hexahydrosiladifenidol

• The apparent dissociation constant values were as follows: atropine (nonselective), 1.95 +/- 0.28 nmol/L; pirenzepine (M1), 169 +/- 24 nmol/L; AF-DX 116 (M2), 1542 +/- 33 nmol/L; and hexahydrosiladifenidol (M3), 29 +/- 3.4 nmol/L [2].
• Therefore, this study was performed to characterize muscarinic receptors on rat gastric parietal cells using the 3 subtype-selective antagonists hexahydrosiladifenidol and silahexocyclium, which have high affinity for glandular M3 subtypes, and AF-DX 116, which has high affinity to cardiac M2 receptors [3].
• To further characterize the population of the smooth muscle receptors recognized as glandular type, we performed protection experiments with hexahydrosiladifenidol, which binds to glandular M3 receptors with high affinity [4].
• AF-DX116 (M2 selective) bound with high affinity to approximately 83% of muscarinic binding sites, and 4-DAMP and HHSiD (M3 antagonists) bound with high affinity to approximately 24 and 28% of muscarinic binding sites, respectively [5].
• The muscarinic antagonists, hexahydrosiladifenidol and pirenzepine, inhibited carbachol-induced phosphatidylethanol formation in a concentration-dependent manner and the inhibitory constants indicated that muscarinic M1 receptors are responsible for the major part of the phospholipase D activation [6].

Anatomical context of hexahydrosiladifenidol

• The affinities of HHSiD, p-F-HHSiD and zamifenacin were, however, lower than those reported in guinea pig trachea [7].
• Hexahydrosiladifenidol did not discriminate between pre- and postjunctional receptors within the same organ but was more potent on the ileum (20-80 times) than on the heart [8].
• On the other hand, the increase in perfusion pressure upon vagus nerve stimulation is caused by a different muscarinic receptor, more sensitive to hexahydrosiladifenidol than to M2-selective antagonists [9].
• The binding of hexahydrosiladifenidol, procyclidine, 4-DAMP (4-diphenylacetoxy-N-methylpiperidine) and AF-DX 116 to muscarinic receptors in the heart, ileum, urinary bladder, parotid gland and cerebral cortex from guinea pig was studied in competition experiments with (-)-[3H]QNB [10].
• In the caudate nucleus: tripinamide: 9.1 [8.9, 9.2]; 4-DAMP: 8.3 [8.2, 8.5]; himbacine: 8.1 [8.0, 8.2]; AQ-RA 741: 8.1 [8.0, 8.3]; hexahydrosiladifenidol: 7.3 [7.2, 7.4]; AF-DX 116: 7.1 [7.0, 7.2]; pirenzepine: 6.7 [6.6, 6.8]; and PD102807: 6.5 [6.2, 6.8] [11].

Associations of hexahydrosiladifenidol with other chemical compounds

• Pirenzepine, hexahydrosiladifenidol, and para-fluoro-hexahydrosiladifenidol, drugs with high affinity for the M1 subtype, were significantly more potent inhibitors of [3H]-QNB binding than the M2 selective drug methoctramine [12].
• 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) [13].
• Hexahydrosiladifenidol and 4-DAMP recognized two classes of muscarinic binding sites in the cortex [10].

Analytical, diagnostic and therapeutic context of hexahydrosiladifenidol

• The increase in perfusion pressure upon nerve stimulation was reduced by atropine (0.01 mumol/l) or hexahydrosiladifenidol (0.1 mumol/l) to approximately 50% and increased by about 50% in the presence of AF-DX 116 (0.1 mumol/l) [9].

References