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PubMed2001

Muscarinic receptors of the M2 subtype in human and bovine trabecular meshwork.

BACKGROUND: The trabecular meshwork is a tissue actively involved in the regulation of intraocular pressure via contractile mechanisms. The present study was performed to investigate the effects of muscarinic m2-receptor antagonists on trabecular meshwork contractility and to identify the m2 muscarinic receptor in human and bovine trabecular meshwork cells. METHODS: Isometric tension measurements of bovine trabecular meshwork strips were performed using a custom-made force length transducer. Western blot and immunoprecipitation analysis was used to detect the m2-receptor proteins in membrane preparations of human and bovine trabecular meshwork cells. RESULTS: Immunoblotting results showed the expression of an m2-receptor protein band at 56 kDa in both human and bovine trabecular meshwork cells. Two different m2-receptor antagonists were tested on trabecular meshwork contractility. After carbachol-induced contraction (10(-6) M set to 100% contractile force), specific m2-receptor antagonists were applied. 3 alpha-Chloroimperaline (10(-6) M) had no effect on the maximal carbachol-induced contraction in trabecular meshwork strips. Methoctramine induced a significant relaxation at concentrations of 10(-7), 10(-6) and 5 x 10(-6) M even in the presence of m1- and m3-receptor antagonists. CONCLUSION: These data indicate that in addition to the m3-receptor subtype present in the trabecular meshwork this tissue also features the m2 receptor. This receptor is partly involved in the regulation of trabecular meshwork contractility, suggesting that outflow facility might be influenced through this receptor.

Animals↗
PubMed1994

3-alpha-Chlorimperialine: an M2-selective muscarinic receptor antagonist that penetrates into brain.

Muscarinic M2 receptors have been found to be severely depleted in post-mortem brains of Alzheimer's patients. This loss of receptor may represent a useful diagnostic marker, if it could be quantitatively imaged with single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. In order to develop a radioligand with selectivity for muscarinic M2 receptors, we now report that 3-alpha-chlorimperialine is a potent M2 receptor antagonist with a Ki of 0.32 nM at M2 receptors, a 12-fold selectivity for M2 over M1 receptors, and a 5-fold selectivity for M2 over M4 receptors. Furthermore, 2% of the injected dose of 3-alpha-chlorimperialine per gram tissue penetrates into brain within 30 min, then washes out gradually. Taken together, these studies demonstrate that 3-alpha-chlorimperialine is a potent M2-selective muscarinic antagonist that penetrates into brain and may be a useful substrate for radioiodination and subsequent imaging of brain muscarinic M2 receptors.

Animals↗
PubMed2006

Selective antagonism activity of alkaloids from bulbs Fritillariae at muscarinic receptors: functional studies.

15 alkaloids were isolated from five Fritillariae species and 6 derivatives were synthesized. Alkaloids having anticholinergic effect on guinea-pig tracheal smooth muscle were screened out and their mechanism was further studied on the cAMP formation in Chinese hamster ovary cells stably expressing human muscarinic M2 receptor (CHO-hM2 cells) and intracellular calcium ([Ca(2+)](i)) transient in Chinese hamster ovary cells stably expressing human muscarinic M3 receptor (CHO-hM3 cells). In normal Krebs-Henseleit (KH) solution, imperialine (15), 3beta-acetylimperialine (16) and sinpeinine A (17) concentration-dependently relaxed 1 microM carbachol-induced contraction of guinea-pig tracheal rings with EC(50) of 4.19, 1.71 and 4.67 microM, respectively. In Ca(2+)-free KH solution, 10 microM 3beta-acetylimperialine (16), imperialine (15) and sinpeinnine A (17) caused 97.42%, 5.45% and 6.55% inhibition, respectively, which indicated that the three components might inhibit muscarinic receptor in different mechanism. Results of muscarinic M2 receptor-inhibited cAMP formation in CHO-hM2 cells showed that imperialine (15) and sinpeinine A (17) could potently elevate the cAMP formation whereas 3beta-acetylimperialine (16) only had weak effect on antagonism of cAMP inhibition. Furthermore, the investigations of muscarinic M3 receptor-stimulated [Ca(2+)](i) transient in CHO-hM3 cells revealed that imperialine (15) and sinpeinine A (17) could not antagonize [Ca(2+)](i) transient, but 3beta-acetylimperialine (16) significantly inhibited [Ca(2+)](i) peak elevation with an IC(50) of 5.26 microM. The functional studies suggest that the mechanism of relaxant action of imperialine (15) and sinpeinine A (17) is due to their selective inhibitory effects on muscarinic M2 receptors and the mechanism of 3beta-acetylimperialine (16) originates from its selective muscarinic M3 receptors antagonism.

Alkaloids↗
PubMed1999

Pre-column derivatization and gas chromatographic determination of alkaloids in bulbs of Fritillaria.

A method of precolumn derivatization GC with FID detection was developed for a simultaneous analysis of five major steroidal alkaloids of Fritillaria species, namely ebeiedine, ebeiedinone, verticine, verticinone and imperialine. Derivatization was carried out by trimethylsilylation of the hydroxyl-containing Fritillaria alkaloids to the corresponding trimethylsilylates with trimethylsilylimidazole. Reaction conditions were optimised and the alkaloids derivatives were characterised by on-line GC-MS. The validated GC method demonstrated a good linearity at the sampling ranges used. This analytical method is simple, convenient and reproducible. The developed assay was successfully applied to the determination of the major pharmacologically active alkaloids in three commonly used antitussive Fritillaria species: F. cirrhosa, F. thunbergii and F. pallidiflora.

Alkaloids↗
PubMed1998

3-Alpha-chloro-imperialine, a potent blocker of cholinergic presynaptic modulation of glutamatergic afferents in the rat neostriatum.

Cortico-thalamic glutamatergic afferents control neuronal activity in the neostriatum. Cholinergic interneurons modulate the activity of medium spiny neurons through both pre- and post-synaptic actions via the activation of muscarinic receptors. The muscarinic pre-synaptic modulation was analyzed electrophysiologically. The transmitter release, induced by 4-AP, was studied and the block of paired pulse facilitation (PPF) by different muscarinic receptor antagonists was analyzed. The GABA(A) antagonist bicuculline isolated the glutamatergic transmission. Muscarinic agonists decreased the frequency of random synaptic potentials induced by 4-AP in about 60% of the cases without changes in input resistance (RN) of the post-synaptic neuron or in the mean amplitude of the synaptic events; indicating a presynaptic action. The administration of both 1 microM carbachol or 20 nM muscarine increased PPF. Muscarinic receptor antagonists blocked this action with a potency order: 3-alpha-chloroimperialine > 4-DAMP>>AFDX-116 > or = gallamine >> pirenzepine. The IC50's for the first three antagonists were (nM): 0.65, 1.1, and 3.0. Their respective Hill coefficients were: 1.9, 1.4, and 1.3. 3-alpha-Chloroimperialine reduced the PPF almost completely. The M3 and the M2 muscarinic receptor antagonists 4-DAMP and AFDX-116, given at saturating concentrations, consistently blocked only a part of the PPF but had additive effects when given together. These data are consistent with the existence of both M2 and M3 muscarinic receptors in striatal glutamatergic afferents.

4-Aminopyridine↗
PubMed1997

Partial synthesis of 3-O-vanilloylveracevine, an insecticidal alkaloid from Schoenocaulon officinale.

3-O-Vanilloylveracevine has been synthesized for the first time in 70% overall yield by conversion of veracevine into its 3-O-(4-benzyloxy-3-methoxybenzoate) followed by catalytic hydrogenation. The insecticidal activity of the semisynthetic substance against three pest species is inferior to that of cevadine and veratridine, the major components of the insecticidal sabadilla alkaloid mixture.

Animals↗
PubMed1999

Subtypes of muscarinic receptors in rat duodenum: a comparison with rabbit vas deferens, rat atria, guinea-pig ileum and gallbladder by using imperialine.

The specific binding of [3H]QNB to rat duodenum smooth muscle membranes was a saturable process and Scatchard transformation of the saturation curves indicated a linear plot (nH = 1.017+/-0.071). The K(D) and Bmax values were 0.168+/-0.025 nM and 46.7+/-8.6 fmol/mg protein, respectively. Analyses of competition curves using pirenzepine and guanylpirenzepine indicated more than one class of binding site. A minor population of muscarinic binding sites showed high affinity (M1) for both pirenzepine (19.3+/-1.2%; pKi = 8.29+/-0.36) and guanylpirenzepine (29.4+/-2.0%; pKi = 7.28+/-0.11). The antagonistic affinity values of pirenzepine and guanylpirenzepine for the remaining low affinity binding sites, and that of methoctramine indicated the presence of both M2 and M3 subtypes. McN-A-343 produced relaxations in rat duodenum and inhibited twitch contractions of rabbit vas deferens induced by electrical stimulation in a concentration dependent manner. Carbachol (Cch) exerted concentration-dependent negative inotropic effect in rat atria and contractile effects in guinea-pig gallbladder and ileum longitudinal muscle-myenteric plexus preparation. Imperaline displaced the concentration-response curves to McN-A-343 and Cch to the right in parallel, without affecting the maximum responses in all tissues studied. The rank order of the pA2 values was rabbit vas deferens > rat atria > guinea-pig gallbladder = guinea-pig ileum > rat duodenum. The presynaptic muscarinic receptors at the rat duodenum and rabbit vas deferens were concluded to be of M1 and M4 subtypes, respectively.

Animals↗
PubMed2004

Sabadinine: a potential non-peptide anti-severe acute-respiratory-syndrome agent identified using structure-aided design.

A novel human coronavirus has been reported to be the causative agent of severe acute respiratory syndrome (SARS). Since replication of HcoVs depends on extensive proteolytic processing, the main proteinase, 3CLpro, is an attractive drug target for anti-SARS agents. We have employed molecular docking of a chemical database into the active site of 3CLpro to search for non-peptidyl inhibitors. One compound was identified to be the natural product sabadinine, isolated from a historical herbal remedy.

Antiviral Agents↗
PubMed1995

Puqiedinone, a novel 5 alpha-cevanine alkaloid from the bulbs of Fritillaria puqiensis, an antitussive traditional Chinese medicine.

A novel 5 alpha-cevanine alkaloid, puqiedinone [1], was isolated from the bulbs of Fritillaria puqiensis, a traditional Chinese medicine used widely for its antitussive and expectorant properties. The structure of 1 was assigned as (20R,22S,25R)-20-deoxy-5 alpha-cevanine-3 beta-ol-6-one based on spectral analysis and comparison with the structures of related known compounds. Puqietinone [2] was also identified from the same herbal plant and the structure was revised as (22R,25S)-N-methyl-22,26-epiminocholest-3 beta-ol-6-one based on spectroscopic and X-ray crystallographic methods.

Antitussive Agents↗
PubMed2003

Angiotensin converting enzyme (ACE) inhibitory alkaloids from Fritillaria ussuriensis.

Bioassay-guided fractionation of the BuOH-soluble extract of Fritillaria ussuriensis afforded verticinone ( 1), verticine ( 2), and peimisine ( 3). Purification of these compounds was achieved with the use of various chromatographic methods. The structures of the compounds were identified on the basis of MS and NMR data analysis. Compounds 1 - 3 inhibited angiotensin I converting enzyme activity in a dose-dependent manner, displaying 50 % inhibitory concentration values of 165.0 microM, 312.8 microM, 526.5 microM, respectively. The presence of these active substances may be responsible, at least in part, for the antihypertensive action of the bulbs of Fritillaria ussuriensis.

Alkaloids↗
PubMed2006

Inhibitors of acetylcholine esterase in vitro--screening of steroidal alkaloids from Fritillaria species.

18 alkaloids were successfully isolated from five Fritillaria species and 5 derivatives were synthesized. Their effects on the bioactivity of human whole blood cholinesterase (ChE) were assessed. The results showed that N-demethylpuqietinone, hupeheninoside, ebeiedinone, yibeinoside A and chuanbeinone inhibited the bioactivity of human whole blood ChE at the concentration of 1.0 x 10 ( - 4) M, with the inhibitory effects of 55.5 +/- 2.7 %, 66.8 +/- 2.0 %, 69.0 +/- 1.7 %, 71.2 +/- 1.8 % and 70.7 +/- 3.3 %, respectively. The effects of the five alkaloids on human red blood cell (RBC) acetylcholinesterase (AChE) and human plasma butyrylcholinesterase (BChE) were further studied, and their IC (50) values for human RBC AChE were 6.4 +/- 0.003 microM, 16.9 +/- 0.018 microM, 5.7 +/- 0.004 microM, 6.5 +/- 0.013 microM and 7.7 +/- 0.001 microM, respectively, and the IC50 values for human plasma BChE were 12.5 +/- 0.026 microM, 2.1 +/- 0.005 microM, 5.2 +/- 0.002 microM, 7.3 +/- 0.005 microM and 0.7 +/- 0.001 microM, respectively. These data suggest, therefore, that N-demethylpuqietinone, hupeheninoside, ebeiedinone, yibeinoside A and chuanbeinone have both anti-RBC AChE and anti-plasma BChE activities, N-demethylpuqietinone is a selective inhibitor of AChE, whereas hupeheninoside and chuanbeinone are the selective inhibitors of BChE.

Alkaloids↗
PubMed1998

Structure-activity relationships of imperialine derivatives and their anticholinergic activity.

In order to check the structure-activity relationship and prepare more potent derivatives of imperialine with anticholinergic activity, imperialinol (2), 3 beta-acetoxyimperialine (3), 3 beta-propionoxyimperialine (4), and 3 beta-butyroxyimperialine (5) were prepared. Compounds 4 and 5 displayed better anticholinergic activity against muscarinic receptors of the heart and brain than imperialine (1). The decrease in activity in 2 showed the importance of the 6-keto functionality in imparting the anticholinergic activity.

Alkaloids↗