| In order to identify the mechanism between the acetylcholine M receptor and develop novel chiral drugs ,we Comparatively studied pharmacological profiles of phencynonate hydrochloride, de-methyl phencynonate hydrochloride and its optical isomers. Both 3-methyl-3-azabicyclo (3,3,1) nonanyl -9-α-yl-α-cyclopentyl-α -phenyl-α-glycolate (Phencynonate hydrochloride, CPG) and 3-azabicyclo (3,3,1) nonanyl -9-α-yl-α-cyclopentyl-α-phenyl-α-glycolate (De-methyl phencynonate hydrochloride, DMCPG) are chiral drug with one chiral centre, thus have two optical isomoters respectively. In our papers we tested the affinity and relative efficacy of these chiral drugs by radioligand-binding assay with muscarinic acetylcholine receptors from rat cerebral cortex. The pharmacological activities were assessed in three individual experiments: (1) potentiating the effect of subthreshold hypnotic dose of sodium pentobarbital, (2) inhibiting oxotremorine-induced salivation and (3) inhibiting the contractile response to Carbachol. We found that the order of potency of phencynonate hydrochloride and its optical isomers to inhibit the binding of [3H] quinuclidinyl benzilate ([3H] QNB) was R (-)-CPG (Ki = 46.49 ± 1.27 nmol/1) > CPG (Ki = 271.37 ± 72.3 nmol/1) > S (+)-CPG (Ki= 1263.12 ± 131.64 nmol/1). The results showed that R (-)-CPG had the highest affinity to central muscarinic receptors among the three compounds, but did not show any central depressant effects at dose from 10 to 29.15mg/kg. CPG increased the effects of subthreshold hypnotic dose of sodium pentobarbital induced-sleeping [the ED50 ± 95%CL value was 21.06 ± 3.04 mg/kg]. CPG and R (-)-CPG displayed nearly equipotent effect in depressing oxotremorine-induced salivation [the ED50 ± 95%CL for R (-)and CPG were 1.10 ± 0.28 and 1.07 ± 0.15 mg/kg, respectively], and the contractile response to Carbachol ( pA2 values for R (-) and CPG were 6.84 and 6.80, respectively). S (+) -CPG presented the lowest anticholinergic profiles. These data suggested that R (-)-CPG acted as aneutomer in racemate and a competitive antagonist to acetylcholine muscarinic receptors, the central depressant effects of R (-)-CPG and S (+) -CPG were lower in comparison to its racemate.In the other study R (-)-DMCPG (Kj = 763.75nM) were 4 and 2 fold more potent than DMCPG ( K; = 3186nM) and S (+)-configuration (K; = 1699nM) in inhibiting the binding of [3H] QNB. R (-)- and S (+)-configuration showed positive cooperation (nH >1) to muscarinic receptor, whereas DMCPG revealed negative cooperation (nH0.05). DMCPG and its optical isomers suppressed the guinea pig ileum contractile response to carbachol. The IC50 values were 7.78 X10"9, 1.88 XI0"7 and 1.03X10'7M, respectively. In anti-salivation study, DMCPG and its enantiomers depressed oxotremorine-induced salivation in a dose dependent manner, the order of potency was R (-)-DMCPG (ED50 = 0.44 mg/kg) > DMCPG (ED50 = 2.88 mg/kg) > S (+) -DMCPG (ED50 = 5.05 mg/kg). The results showed that DMCPG and its optical isomers revealed differences in pharmacological potencies as anticholinergic agents, and R (-) configuration was more active than its S (+)-configuration.Further more we comparatively studied the muscarinic subtype receptor selectively effects among R (-) - CPG, R (-) DMCPG and DMCPG. They all selective bound to M4 subtype receptor, the order of potency was R (-) DMCPG (pD2= 8.69)> R (-)-CPG (pD2= 8.31)> DMCPG (pD2 = 7.99), R (-)-CPG showed more potent than the other two compounds to Mi and M3 receptors. It was intresting that R (-) DMCPG displayed the selective between M4/M2 receptors. The results indicated that there are subtype selective action among these compounds. We also investigated the nH values of these compound, the results indicated that allosteric mechanism were related to these chiral drugs, this need to be further explored.The results showed that there were stereoselectivety and subtype selectivety between chiral drugs and receptor target. The M receptor more preferred to be bound by... |
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