Ke-Liang Liu

Pharmacological profiles of an anticholinergic agent, phencynonate hydrochloride, and its optical isomers

AbstractAim:To comparatively study the pharmacological profiles of 3-methyl-3-azabicyclo (3,3,1)nonanyl-9-α-yl-α-cyclopentyl-α-phenyl-α-glycolate (phencynonate hydrochloride, CPG), an anticholinergic agent, and its enantiomers [R(–)- and S(+)-CPG].Methods:The affinity and relative efficacy were tested using 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.Results:The order of potency of phencynonate hydrochloride and its optical isomers to inhibit the binding of [3H]quinucli-dinyl benzilate ([3H]QNB) was R(–)-CPG (Ki=46.49±1.27 nmol/L)>CPG (Ki=271.37± 72.30 nmol/L)>S(+)-CPG (Ki=1263.12±131.64 nmol/L). 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 10.00 to 29.15 mg/kg. CPG increased the effects of subthreshold hypnotic dose of sodium pentobarbital induced-sleeping [the ED50±95% LC value was 21.06±3.04 mg/kg]. CPG and R(–)-CPG displayed nearly equipotent effect in depressing oxotremorineinduced salivation [the ED50± 95% LC 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, but could potentate effects of its enantiomers in some manner.Conclusions:These data suggested that R(–)-CPG acted as an eutomer in racemate and a competitive antagonist to acetylcholine muscarinic receptors, but S(+)-CPG was less active in comparison to R(–)-CPG and its racemate. The central depressant effects of R(–)-CPG and S(+)-CPG were lower in comparison to its racemate.

Optical Resolution, Stereoselective Synthesis, and Crystal Structure of 9α‐(3‐Azabicyclo[3,3,1]nonanyl)‐2′‐cyclopentyl‐2′‐hydroxy‐2′‐phenylacetate

Abstract 9α‐(3‐Azabicyclo[3,3,1]nonanyl)‐2′‐cyclopentyl‐2′‐hydroxy‐2′‐phenylacetate (1) was synthesized and its enantiomers were obtained by the optical resolution of racemates with the chiral host N‐p‐toluenesulfonylglutamic acid. Optical pure 1 was also effective diastereoselective synthesized using benzaldehye as steric hindrance agent from the chiral starting material, (S) or (R)‐mandelic acid. The structure of the title compound was first elucidated by X‐ray analysis.

Studies on crystal structure of inclusion chiral crystal of (S)-α-cyclopentyl- α-hydroxyl-α-thienylacetic acid with (R)-α-methyl benylamine

The optically active α-cyclopentyl- α-hydroxyl-α-thienylacetic acid is obtained by the optical resolution of racemates with the chiral host α-methylbenylamine. The structure of the inclusion salt complex of two compounds was first elucidated by X-ray analysis.

Comparative study on pharmacological effects of DM-phencynonate hydrochloride and its optical isomers

AbstractAim:The 3-azabicyclo(3,3,1)nonanyl-9-α-yl-α -cyclopentyl-α -phenyl-α -glycolate (DM-phencynonate hydrochloride, DMCPG) is a demethylated metabolite of 3- methyl-3-azabicyclo(3,3,1)nonanyl-9-α-yl-α-cyclopentyl-α-phenyl-α-glycolate (phencynonate hydrochloride, CPG). (±)DMCPG had one chiral center and two enantiomers [R(-) and S(+)DMCPG]. Here we carried out a comparative study of the pharmacological profiles of these optical isomers.Methods:Affinity and relative efficacy were tested using a radioligand-binding assay with muscarinic acetylcholine receptors from the rat cerebral cortex. Pharmacological activity was assessed in three individual experiments: (1) potentiating the effect of a subthreshold hypnotic dose of sodium pentobarbital; (2) inhibiting oxotremorine- induced salivation; and (3) inhibiting the contractile response to carbachol.Results:In the competitive binding assay, R(−)DMCPG (Ki=763.75 nmol/L) was 4- and 2-fold more potent than (±)DMCPG (Ki=3186 nmol/L) and S(+)DMCPG (Ki=1699 nmol/L) in inhibiting the binding of [3H]QNB. The R(−) and S (+) configurations showed positive cooperation (nH>1) with the muscarinic receptor, whereas (±)DMCPG had a negative cooperation (nH<1) relationship with the muscarinic receptor in a radio-binding assay. Both the R(−) and S(+) configurations could potentiate the effect of sub-threshold hypnotic dose of sodium pentobarbital in a dose-dependent manner (the ED50 values were 2.53 and 18.65 mg/kg, respectively), but (±)DMCPG did not display significant central depressant effects at doses from 10 to 29.15 mg/kg (P>0.05). (±)DMCPG and its optical isomers suppressed the guinea pig ileum contractile response to carbachol. The IC50 values were 7.78×10−9, 1.88×10−7, and 1.03×10−7 nmol/L, respectively. In the anti-salivation study, (±)DMCPG and its enantiomers depressed oxotremorine- induced salivation in a dose-dependent manner, and 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).Conclusion:(±)DMCPG and its optical isomers have differences in their pharmacological potencies as anticholinergic agents, and the R(−) configuration is more active than the S(+) configuration.

Stereoselective synthesis of 3-azabicyclo[3,3,1]nonan-9a-yl α-(cyclopentyl-1-ene)-α-hydroxy-a-phenylacetate hydrochloride

The isomers of α-(cyclopentyl-1-ene)-α-hydroxy-α-phenylacetic acid esters derived from 3-azabicyclo[3,3,1]nonan-9α-ol ((R)-1 and (S)-1) were obtained in high enantiomeric excess by effective stereoselective synthesis from the chiral starting material, (S) or (R)-mandelic acid using pivaldehyde as a sterically hindered reagent

Stereoselective synthesis of α-alkyl-α-hydroxylphenylacetic acid

An effective asymmetric synthesis of α-alkyl-α-hydroxyl phenyl acetic acid using benzaldehyde as steric hindrance agent has been accomplished by utilising the readily available and inexpensive chiral starting material, (S)-mandelic acid. The ee was determined by 1H NMR with Eu(hfc)3 as shift reagent.

Stereoselective Synthesis of the Optical Isomers of a New Muscarinic Receptor Antagonist, HL‐031120

Abstract We present here a practical stereoselective synthetic method to produce enantiopure isomers of a new muscarinic receptor antagonist, HL‐031120 (3‐quinuclidinyl‐2′‐cyclopentyl‐2′‐hydroxy‐2′‐phenylacetate, I). Four optical isomers were effectively by stereoselective synthesized using pivaldehyde as steric hindrance agent from the chiral starting material, (S) or (R)‐mandelic acid. The isomers were obtained with 70–76% yields in 98–99% e.e.

Synthesis and crystal structure of quinuclidin-3-yl 2-cyclopentyl-2-hydroxy-2-phenylacetate

Quinuclidin-3-yl 2-cyclopentyl-2-hydroxy-2-phenylacetate, a more effective the muscarinic receptor antagonist, was synthesised and its crystal structure was first elucidated by X-ray crystallography.

Synthesis and crystal structure of (9s)-N-methyl-3-azabicyclo[3.3.1]nonan-9-yl (cyclopentyl)(hydroxy)(2-thienyl)acetate hydrochloride

(9s)-N-methyl-3-azabicyclo[3.3.1]nonan-9-yl (cyclopentyl)(hydroxy)(2-thienyl)acetate hydrochloride, a more effective muscarinic receptor antagonist, was synthesised and its crystal structure elucidated by X-ray crystallography.

Stereoselective synthesis of the optical isomers of a new muscarinic receptor antagonist, quinuclidin-3-yl 2-(cyclopent-1-enyl)-2-hydroxy-2-phenylacetate

The enantiopure isomers of a new muscarinic receptor antagonist, quinuclidin-3-yl 2- (cyclopent-1-enyl)-2-hydroxy-2-phenylacetate were synthesised by a practical stereoselective synthetic method, using pivaldehyde as steric hindrance agent from the chiral starting material, (S) or (R)-mandelic acid. The isomers were obtained with 72–78 % yields in 98–99 % e.e.