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Christoph Seyfried - One of the best experts on this subject based on the ideXlab platform.
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sarizotan a serotonin 5 ht1a receptor agonist and dopamine receptor ligand 1 neurochemical profile
Journal of Neural Transmission, 2004Co-Authors: Gert Bartoszyk, C Van Amsterdam, Hartmut Greiner, Wilfried Rautenberg, H Russ, Christoph SeyfriedAbstract:Sarizotan exhibited high affinities only to serotonin 5-HT1A receptors and dopamine DA D4>D3>D2 receptors with the profile of a 5-HT1A agonist and DA antagonist demonstrated by the inhibition of cAMP-stimulation and guinea pig Ileum Contraction, decreased accumulation of the 5-HT precursor 5-hydroxytryptophan and increased levels of 5-HT metabolites, increased accumulation of DA precursor dihydroxyphenylalanine (DOPA) and the reduced levels of DA metabolites in intact rats. However, sarizotan at higher doses decreased DA precursor accumulation in reserpinized rats and induced contralateral rotational behavior in unilaterally substantia nigra lesioned rats, indicating some intrinsic dopaminergic activity; at D2 receptors sarizotan may act as a partial agonist, depending on the dopaminergic impulse flow. Sarizotan represents a new approach for the treatment of extrapyramidal motor complications such as l-DOPA-induced dyskinesia in Parkinson’s disease.
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Sarizotan, a serotonin 5-HT_1A receptor agonist and dopamine receptor ligand. 1. Neurochemical profile
Journal of Neural Transmission, 2004Co-Authors: Gert Bartoszyk, C Van Amsterdam, Wilfried Rautenberg, H Russ, H. E. Greiner, Christoph SeyfriedAbstract:Sarizotan exhibited high affinities only to serotonin 5-HT_1A receptors and dopamine DA D_4>D_3>D_2 receptors with the profile of a 5-HT_1A agonist and DA antagonist demonstrated by the inhibition of cAMP-stimulation and guinea pig Ileum Contraction, decreased accumulation of the 5-HT precursor 5-hydroxytryptophan and increased levels of 5-HT metabolites, increased accumulation of DA precursor dihydroxyphenylalanine (DOPA) and the reduced levels of DA metabolites in intact rats. However, sarizotan at higher doses decreased DA precursor accumulation in reserpinized rats and induced contralateral rotational behavior in unilaterally substantia nigra lesioned rats, indicating some intrinsic dopaminergic activity; at D_2 receptors sarizotan may act as a partial agonist, depending on the dopaminergic impulse flow. Sarizotan represents a new approach for the treatment of extrapyramidal motor complications such as l-DOPA-induced dyskinesia in Parkinson’s disease.
Gholam-reza Asghari - One of the best experts on this subject based on the ideXlab platform.
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Study of antispasmodic action of Lavandula angustifolia Mill hydroalcoholic extract on rat Ileum
Journal of Herbmed Pharmacology, 2019Co-Authors: Hassan Sadraei, Gholam-reza Asghari, Mojtaba RahmatiAbstract:Introduction: Lavender (Lavandula angustifolia Mill) is a herbal medicine widely used for gastrointestinal (GI) disorders. However, its pharmacological action on isolated Ileum has not been studied. In this research effect of hydroalcoholic extract of L. angustifolia on isolate Ileum Contractions was studies and compared with loperamide.Methods: Hydroalcoholic extract of the plant was prepared by percolation method. The total flavonoid contents were assessed by colorimetric technique. A portion of rat Ileum was suspended in an organ bath containing Tyrode’s solution. The tissue was kept under 1 g tension at 37°C and continuously gassed with O2. The tissue was stimulated with KCl (80 mM), acetylcholine (ACh, 2 μM) and electrical field stimulation (EFS). Effect of the L. angustifolia extract was studied on Ileum Contractions and compared with that of loperamide.Results: The yield of hydroalcoholic extract was 17% with total flavonoid content of 185 μg/mL in the stock solution. Loperamide in concentration dependent manner inhibited Ileum contractile response to KCl, ACh and EFS. Hydroalcoholic extract of L. angustifolia (8-512 μg/mL) concentration dependently inhibited Ileum Contraction induced by KCl (IC50 = 88 ± 21 μg/mL), ACh (IC50 = 119 ± 251 μg/mL) and EFS (IC50 = 87 ± 33 μg/mL). The vehicle had no significant effect on Ileum Contractions.Conclusion: From this study it was concluded that L. angustifolia extract at microgram concentration shows an inhibitory effect on rat Ileum smooth muscle. Therefore, isolation and identification of active ingredients are recommended.
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Assessment of hydroalcoholic and hexane extracts of Rosa persica Mich. flower on rat Ileum spasm.
Research in pharmaceutical sciences, 2016Co-Authors: Hassan Sadraei, Gholam-reza Asghari, Fatemeh JalaliAbstract:It has been reported that Rosa damascena hydroalcoholic extract has inhibitory effect at higher concentration but stimulatory action at lower concentrations on Ileum. This could be due to the presence of stimulatory components in the extract. R. persica Mich. is another species which belongs to Rose family but so far there is no report about pharmacological action of its extract. Therefore, the objective of this research was to investigate inhibitory effect of hydroalcoholic and hexane extract of this plant on Ileum Contraction to see which type of extract would be more appropriate as antispasmodic agents. Hydroalcoholic and hexane extracts were prepared by percolation method. A section of rat Ileum was suspended in an organ bath containing Tyrode's solution. The tissue was kept under 1 g tension at 37°C and continuously gassed with O2. Effects of R. persica extracts or vehicle were studied on Ileum Contractions induced by electrical field stimulation (EFS), KCl or acetylcholine (ACh) and compared with that of atropine. Hydroalcoholic extracts of R. persica (10-640 μg/ml) concentration dependently inhibited Ileum Contraction induced by KCl (IC50 = 244 ± 35 μg/ml), ACh (IC50 = 129 ± 7.4 μg/ml) and EFS (IC50 = 172 ± 18.7 μg/ml). Hexane extract of R. persica (10-320 μg/ml) concentration dependently inhibited Ileum Contraction induced by KCl (IC50 = 117 ± 12.4 μg/ml), ACh (IC50 = 78 ± 9.1 μg/ml) and EFS (IC50 = 67 ± 10.5 μg/ml). Atropine only inhibited the responses to ACh and EFS. The vehicle had no significant effect on Ileum Contractions. From this experiment it was concluded that R. persica extract have inhibitory effect on rat isolated Ileum. Therefore, separation and identification of active component is recommended.
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Antispasmodic effect of Dracocephalum kotschyi hydroalcoholic extract on rat Ileum Contraction
Research in Pharmaceutical Sciences, 2015Co-Authors: Hassan Sadraei, Gholam-reza Asghari, Faezeh KasiriAbstract:Dracocephalum kotschyi Boiss. (Labiatae) is a traditional medicine which is believed to have antispasmodic and analgesic activities. The antispasmodic action of D. kotschyi essential oil has been shown in a previous report. The objective of this research was to study antispasmodic activity of hydroalcoholic extract of D. kotschyi on Ileum Contractions. Hydroalcoholic extract was obtained from aerial part of D. kotschyi using percolation method. For antispasmodic studies, a portion of rat Ileum was suspended under 1g tension in Tyrode's solution at 37 °C and gassed with O2. Effect of the D. kotschyi extract was assessed on Ileum Contractions induced by KCl (80 mM), acetylcholine (ACh, 500 nM) and electrical field stimulation (EFS). The D. kotschyi extract concentration dependently inhibited the response to KCl (IC50 =36 ± 5.1 μg/ml), ACh (IC50 =101 ± 9.5 μg/ml), EFS-1 (IC50 =96 ± 7.1 μg/ml) and EFS-2 (IC50 =53 ± 4.3 μg/ml). From this experiment it was concluded that D. kotschyi extract possessed potent antispasmodic activity. Therefore, identification of the active component(s) is (are) recommended in order to find the best lead compound for drug development.
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Assessment of hydroalcoholic extract of seeds and leaves of Moringa peregrina on Ileum spasm
Research in pharmaceutical sciences, 2015Co-Authors: Hassan Sadraei, Gholam-reza Asghari, F FarahnakiAbstract:Seeds of Moringa peregrina (Forssk.) Fiori. (Moringaceae) is widely used in south east of Iran for gastrointestinal disorders. However, so far there is no pharmacological evidence for antispasmodic activity of this plant extract. Therefore, the aim of this research was to investigate antispasmodic activity of M. peregrina on rat isolated Ileum Contraction. Hydroalcoholic extract was obtained by percolation method from seeds and leaves of M. peregrina collected from Baluchestan province of Iran. A portion of isolated rat Ileum was suspended under 1 g tension in Tyrode's solution at 37 °C and gassed with O2. Effects of seeds and leaves extracts of M. peregrina were studied on Ileum Contractions induced by KCl (80 mM), acetylcholine (ACh, 250 μM) and electrical field stimulation (EFS). The seed extract of M. peregrina concentration dependently inhibited the response to KCl (IC50=87 ± 18 μg/ml), ACh (IC50=118 ± 18 μg/ml) and EFS (IC50=230 ± 51 μg/ml). The extract of M. peregrina leaves also had inhibitory effect of Ileum Contraction induced by KCl (IC50=439 ± 108 μg/ml), ACh (IC50=365 ± 61 μg/ml) or EFS (IC50=314 ± 92 μg/ml). From these experiments it was concluded that M. peregrina extract mainly had an inhibitory effect on Ileum Contractions but the seed extract was more potent than the leave extract in inhibiting KCl and ACh contractile responses.
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Evaluation of anti-spasmodic effect of Peucedanum pastinacifolium extracts on rat’s Ileum
Research in pharmaceutical sciences, 2015Co-Authors: Hassan Sadraei, Gholam-reza Asghari, Monireh MotaqediAbstract:Genus Peucedanum belongs to the subfamily of Apioideae (Umbelliferae family) and is reported to have many medicinal properties. Several spiecis of Peucedum reported to have antispasmodic activity. Peucedanum pastinacifolium species grows in Iran. However, so far there is no report on its antispasmodic activity. The objective of this research was to investigate antispasmodic activities of P. pastinacifolium extract using in vitro isolated tissue techniques. Hydroalcoholic and hexanoic extracts were prepared by perculation method from aerial part of P. pastinacifolium. A portion of rat isolated Ileum was suspended under 1g tension in Tyrode's solution at 37 °C and gassed with O2. Effects of extracts of P. pastinacifolium were studied on Ileum Contractions induced by KCl (80 mM), acetylcholine (ACh, 250 µM) and electrical field stimulation (EFS). The hydroalcoholic extract P. pastinacifolium concentration dependently inhibited the response to KCl (IC50 =220 ± 30 μg/ml), ACh (IC50 =175 ± 15 μg/ml) and EFS (IC50 =95 ± 15 μg/ml). The hexanoic extract of P. pastinacifolium also had inhibitory effect on Ileum Contraction induced by KCl (IC50 =16 ± 2 μg/ml), ACh (IC50 =30 ± 5 μg/ml) or EFS (IC50 =11 ± 4 μg/ml). From these experiments it was concluded that both hydroalcoholic and hexanoic extract of P. pastinacifolium contain substances which have antispasmodic activities but these substances are mainly concentrated in the hexanoic extract.
Hassan Sadraei - One of the best experts on this subject based on the ideXlab platform.
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Study of antispasmodic action of Lavandula angustifolia Mill hydroalcoholic extract on rat Ileum
Journal of Herbmed Pharmacology, 2019Co-Authors: Hassan Sadraei, Gholam-reza Asghari, Mojtaba RahmatiAbstract:Introduction: Lavender (Lavandula angustifolia Mill) is a herbal medicine widely used for gastrointestinal (GI) disorders. However, its pharmacological action on isolated Ileum has not been studied. In this research effect of hydroalcoholic extract of L. angustifolia on isolate Ileum Contractions was studies and compared with loperamide.Methods: Hydroalcoholic extract of the plant was prepared by percolation method. The total flavonoid contents were assessed by colorimetric technique. A portion of rat Ileum was suspended in an organ bath containing Tyrode’s solution. The tissue was kept under 1 g tension at 37°C and continuously gassed with O2. The tissue was stimulated with KCl (80 mM), acetylcholine (ACh, 2 μM) and electrical field stimulation (EFS). Effect of the L. angustifolia extract was studied on Ileum Contractions and compared with that of loperamide.Results: The yield of hydroalcoholic extract was 17% with total flavonoid content of 185 μg/mL in the stock solution. Loperamide in concentration dependent manner inhibited Ileum contractile response to KCl, ACh and EFS. Hydroalcoholic extract of L. angustifolia (8-512 μg/mL) concentration dependently inhibited Ileum Contraction induced by KCl (IC50 = 88 ± 21 μg/mL), ACh (IC50 = 119 ± 251 μg/mL) and EFS (IC50 = 87 ± 33 μg/mL). The vehicle had no significant effect on Ileum Contractions.Conclusion: From this study it was concluded that L. angustifolia extract at microgram concentration shows an inhibitory effect on rat Ileum smooth muscle. Therefore, isolation and identification of active ingredients are recommended.
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Assessment of hydroalcoholic and hexane extracts of Rosa persica Mich. flower on rat Ileum spasm.
Research in pharmaceutical sciences, 2016Co-Authors: Hassan Sadraei, Gholam-reza Asghari, Fatemeh JalaliAbstract:It has been reported that Rosa damascena hydroalcoholic extract has inhibitory effect at higher concentration but stimulatory action at lower concentrations on Ileum. This could be due to the presence of stimulatory components in the extract. R. persica Mich. is another species which belongs to Rose family but so far there is no report about pharmacological action of its extract. Therefore, the objective of this research was to investigate inhibitory effect of hydroalcoholic and hexane extract of this plant on Ileum Contraction to see which type of extract would be more appropriate as antispasmodic agents. Hydroalcoholic and hexane extracts were prepared by percolation method. A section of rat Ileum was suspended in an organ bath containing Tyrode's solution. The tissue was kept under 1 g tension at 37°C and continuously gassed with O2. Effects of R. persica extracts or vehicle were studied on Ileum Contractions induced by electrical field stimulation (EFS), KCl or acetylcholine (ACh) and compared with that of atropine. Hydroalcoholic extracts of R. persica (10-640 μg/ml) concentration dependently inhibited Ileum Contraction induced by KCl (IC50 = 244 ± 35 μg/ml), ACh (IC50 = 129 ± 7.4 μg/ml) and EFS (IC50 = 172 ± 18.7 μg/ml). Hexane extract of R. persica (10-320 μg/ml) concentration dependently inhibited Ileum Contraction induced by KCl (IC50 = 117 ± 12.4 μg/ml), ACh (IC50 = 78 ± 9.1 μg/ml) and EFS (IC50 = 67 ± 10.5 μg/ml). Atropine only inhibited the responses to ACh and EFS. The vehicle had no significant effect on Ileum Contractions. From this experiment it was concluded that R. persica extract have inhibitory effect on rat isolated Ileum. Therefore, separation and identification of active component is recommended.
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Antispasmodic effect of Dracocephalum kotschyi hydroalcoholic extract on rat Ileum Contraction
Research in Pharmaceutical Sciences, 2015Co-Authors: Hassan Sadraei, Gholam-reza Asghari, Faezeh KasiriAbstract:Dracocephalum kotschyi Boiss. (Labiatae) is a traditional medicine which is believed to have antispasmodic and analgesic activities. The antispasmodic action of D. kotschyi essential oil has been shown in a previous report. The objective of this research was to study antispasmodic activity of hydroalcoholic extract of D. kotschyi on Ileum Contractions. Hydroalcoholic extract was obtained from aerial part of D. kotschyi using percolation method. For antispasmodic studies, a portion of rat Ileum was suspended under 1g tension in Tyrode's solution at 37 °C and gassed with O2. Effect of the D. kotschyi extract was assessed on Ileum Contractions induced by KCl (80 mM), acetylcholine (ACh, 500 nM) and electrical field stimulation (EFS). The D. kotschyi extract concentration dependently inhibited the response to KCl (IC50 =36 ± 5.1 μg/ml), ACh (IC50 =101 ± 9.5 μg/ml), EFS-1 (IC50 =96 ± 7.1 μg/ml) and EFS-2 (IC50 =53 ± 4.3 μg/ml). From this experiment it was concluded that D. kotschyi extract possessed potent antispasmodic activity. Therefore, identification of the active component(s) is (are) recommended in order to find the best lead compound for drug development.
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Comparison of antispasmodic effects of Dracocephalum kotschyi essential oil, limonene and α-terpineol.
Research in Pharmaceutical Sciences, 2015Co-Authors: Hassan Sadraei, G Asghari, Faezeh KasiriAbstract:Dracocephalum kotschyi is an essential oil containing plant found in Iran. In Iranian traditional medicine, D. kotschyi has been used as antispasmodic and analgesic but so far there is no pharmacological report about its antispasmodic activity. Therefore, the objective of this research was to study antispasmodic activity of the essential oil of D. kotschyi and two of its constituents namely limonene and a-terpineol. The essential oil was obtained from aerial parts of D. kotschyi using hydrodistillation method. The main components found in the essential oil were a-pinene (10%), neral (11%), geraniol (10%), a-citral (12%), limonene (9%) and a-terpineol (1.1%). For antispasmodic studies, a portion of rat Ileum was suspended under 1 g tension in Tyrode’s solution at 37 °C and gassed with O 2 . Effect of the D. kotschyi essential oil, limonene and a-terpineol were studied on Ileum Contractions induced by KCl (80 mM), acetylcholine (ACh, 500 nM) and electrical field stimulation (EFS). The essential oil, in a concentration dependent manner inhibited the response to KCl (IC 50 =51 ± 8.7 nl/ml), ACh (IC 50 =19 ± 2.7 nl/ml) and EFS (IC 50 =15 ± 0.5 nl/ml). Limonene and a-terpineol showed same pattern of inhibitory effect on Ileum Contraction. Their inhibitory effects were also concentration dependent. However, limonene was more potent than the essential oil while the a-terpineol was less potent than either limonene or the essential oil. From this experiment it was concluded that D. kotschyi essential oil has inhibitory effect on Ileum Contractions. Limonene contribute a major role in inhibitory effect of the essential oil while a-terpineol has weak antispasmodic activity.
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Assessment of hydroalcoholic extract of seeds and leaves of Moringa peregrina on Ileum spasm
Research in pharmaceutical sciences, 2015Co-Authors: Hassan Sadraei, Gholam-reza Asghari, F FarahnakiAbstract:Seeds of Moringa peregrina (Forssk.) Fiori. (Moringaceae) is widely used in south east of Iran for gastrointestinal disorders. However, so far there is no pharmacological evidence for antispasmodic activity of this plant extract. Therefore, the aim of this research was to investigate antispasmodic activity of M. peregrina on rat isolated Ileum Contraction. Hydroalcoholic extract was obtained by percolation method from seeds and leaves of M. peregrina collected from Baluchestan province of Iran. A portion of isolated rat Ileum was suspended under 1 g tension in Tyrode's solution at 37 °C and gassed with O2. Effects of seeds and leaves extracts of M. peregrina were studied on Ileum Contractions induced by KCl (80 mM), acetylcholine (ACh, 250 μM) and electrical field stimulation (EFS). The seed extract of M. peregrina concentration dependently inhibited the response to KCl (IC50=87 ± 18 μg/ml), ACh (IC50=118 ± 18 μg/ml) and EFS (IC50=230 ± 51 μg/ml). The extract of M. peregrina leaves also had inhibitory effect of Ileum Contraction induced by KCl (IC50=439 ± 108 μg/ml), ACh (IC50=365 ± 61 μg/ml) or EFS (IC50=314 ± 92 μg/ml). From these experiments it was concluded that M. peregrina extract mainly had an inhibitory effect on Ileum Contractions but the seed extract was more potent than the leave extract in inhibiting KCl and ACh contractile responses.
Seyed Ahmad Emami - One of the best experts on this subject based on the ideXlab platform.
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Effect of Rosa damascena Mill. flower extract on rat Ileum.
Research in Pharmaceutical Sciences, 2013Co-Authors: Hassan Sadraei, Gholam-reza Asghari, Seyed Ahmad EmamiAbstract:Rosa damascena flower is widely used for gastrointestinal (GI) disorders. However, its pharmacological action on isolated Ileum has not been studied. In this research, the effect of extract of flower petals of R. damascena Mill. growing in Kashan, Iran, on Ileum motility was investigated. Hydroalcoholic extract was prepared by percolation method. A section of rat Ileum was suspended in an organ bath containing Tyrode’s solution. The tissue was stimulated with electrical field stimulation (EFS), KCl and acetylcholine (ACh). The tissue was kept under 1g tension at 37°C and continuously gassed with O2. Effect of the R. damascena extract was studied on Ileum Contractions induced by EFS, KCl and ACh and compared with that of atropine. R. damascena extract (10-100 µg/ml) induced a Contraction in rat isolated Ileum while at 1mg bath concentration it had relaxant effect on rat Ileum. Hydroalcoholic extract of R. damascena (1-8 mg/ml) concentration dependently inhibited Ileum Contraction induced by KCl (IC50=3.3 ± 0.9 mg/ml), ACh (IC50=1.4 ± 0.1 mg/ml) and EFS (IC50=1.5 ± 0.3 mg/ml). The vehicle had no significant effect on Ileum Contractions. From this experiment it was concluded that R. damascena extract at microgram concentrations had stimulatory effect on Ileum smooth muscle. However, at milligram concentrations, it shows an inhibitory effect. This is most likely due to presence of different components in the extract. The stimulatory effect of the extract confirms its benefits for the treatment of constipation. Therefore, separation and identification of active components is recommended.
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inhibitory effect of rosa damascena mill flower essential oil geraniol and citronellol on rat Ileum Contraction
Research in Pharmaceutical Sciences, 2013Co-Authors: H Sadraei, Gholam-reza Asghari, Seyed Ahmad EmamiAbstract:Flower of Rosa damascena Mill is widely used in Iran for gastrointestinal (GI) disorders. However, its pharmacological action on Ileum Contraction has not been studied. In this research we have investigated Ileum motility effect of essential oil of flower petals of R. damascena growing in Kashan, Iran, and two of its constituents. The essential oils obtained by hydrodistillation were investigated by a combination of GC and GC/MS. More than 34 compounds have been identified. The main constituents of the essential oil were β-citronellol (23%), nonadecane (16%), geraniol (16%) and heneicosane (5%). A portion of rat isolated Ileum was suspended under 1g tension in Tyrode's solution at 37°C and gassed with O2. Effect of the R. damascena essential oil (2.5-160 μg/ml), geraniol (0.2-3.2 μg/ml) and citronellol (0.8-6.4 μg/ml) were studied on Ileum Contractions induced by KCl, acetylcholine (ACh) and electrical field stimulation (EFS) and compared with standard drugs atropine and loperamide. The contractile response of EFS was mediated mainly through the intramural nerve plexuses, because its response was inhibited by loperamide and partially reduced by atropine. The essential oil concentration dependently inhibited the response to KCl (IC50=67 ± 8.4μg/ml) and EFS (IC50=47 ± 10.6 μg/ml). Geraniol (IC50=1.7 ± 0.15 μg/ml for KCl) and citronellol (IC50=2.9 ± 0.3 μg/ml for KCl) also had inhibitory effect of Ileum Contraction and both were more potent than the essential oil. It was concluded that R. damascena essential oil mainly had an inhibitory effect on Ileum Contractions and geraniol and citronellol had a major role in inhibitory effect of the essential.
Haruhide Kimura - One of the best experts on this subject based on the ideXlab platform.
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an approach to discovering novel muscarinic m1 receptor positive allosteric modulators with potent cognitive improvement and minimized gastrointestinal dysfunction
Journal of Pharmacology and Experimental Therapeutics, 2018Co-Authors: Emi Kurimoto, Yuu Sako, Takao Mandai, Hiroki Sakamoto, Takahiro Sugimoto, Yuji Shimizu, Satoru Matsuda, Haruhide KimuraAbstract:Activation of muscarinic M1 receptor (M1R) is a promising approach for improving cognitive impairment in Alzheimer’s disease. However, an M1R-selective positive allosteric modulator (PAM), benzyl quinolone carboxylic acid (BQCA), at 30 mg/kg, induced diarrhea in wild-type mice, but not in M1R knockout mice. Moreover, BQCA (0.1–1000 nM) augmented electric field stimulation (EFS)-induced Ileum Contraction in an in vitro Magnus assay. Thus, we decided to establish a drug-screening strategy to discover novel M1 PAMs producing potent cognitive improvement with minimized gastrointestinal (GI) dysfunction. We assessed PAM parameters of various M1 PAMs with ≥100-fold selectivity over other muscarinic receptor subtypes by using in vitro binding and functional analysis. Evaluation of these M1 PAMs in the Magnus assay revealed a significant correlation between percentage of Ileum Contractions at 1 μM and their α-value, a PAM parameter associated with the binding cooperativity between acetylcholine and M1 PAM. M1 PAMs with lower α-value showed lower impact on EFS-induced Ileum Contraction. Next, we characterized in vivo profiles of two M1 PAMs: compound A (log α = 1.18) and compound B (log α = 3.30). Compound A, at 30 mg/kg, significantly improved scopolamine-induced cognitive deficits without prominent signs of diarrhea at up to 1000 mg/kg in mice. In contrast, compound B, at 10 mg/kg, showed both significant improvement of scopolamine-induced cognitive deficits and severe diarrhea. Thus, fine adjustment of the α-values could be a key to discovering M1 PAMs yielding potent cognitive improvement with a lower risk of GI effects.
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An Approach to Discovering Novel Muscarinic M1 Receptor Positive Allosteric Modulators with Potent Cognitive Improvement and Minimized Gastrointestinal Dysfunction.
Journal of Pharmacology and Experimental Therapeutics, 2017Co-Authors: Emi Kurimoto, Yuu Sako, Takao Mandai, Hiroki Sakamoto, Takahiro Sugimoto, Yuji Shimizu, Satoru Matsuda, Haruhide KimuraAbstract:Activation of muscarinic M1 receptor (M1R) is a promising approach for improving cognitive impairment in Alzheimer9s disease. However, an M1 selective positive allosteric modulator (PAM), benzyl quinolone carboxylic acid (BQCA), at 30 mg/kg, induced diarrhea in wild-type mice, but not in M1R knock-out mice. Moreover, BQCA (0.1-1000 nM) augmented electric field stimulation (EFS) -induced Ileum Contraction in an in vitro Magnus assay. Thus, we decided to establish a drug-screening strategy to discover novel M1 PAMs producing potent cognitive improvement with minimized gastrointestinal (GI) dysfunction. We assessed PAM parameters of various M1 PAMs with ≥ 100-fold selectivity over other muscarinic receptor subtypes by using in vitro binding and functional analysis. Evaluation of these M1 PAMs in the Magnus assay revealed a significant correlation between % of Ileum Contractions at 1 μM and their α-value, a PAM parameter associated with the binding cooperativity between acetylcholine and M1 PAM. M1 PAMs with lower α-value showed lower impact on EFS-induced Ileum Contraction. Next, we characterized in vivo profiles of two M1 PAMs: compound A (log α = 1.18) and compound B (log α = 3.30). Compound A, at 30 mg/kg, significantly improved scopolamine-induced cognitive deficits without prominent signs of diarrhea at up to 1000 mg/kg in mice. In contrast, compound B, at 10 mg/kg, showed both significant improvement of scopolamine-induced cognitive deficits and severe diarrhea. Thus, fine adjustment of the α-values could be a key to discovering M1 PAMs yielding potent cognitive improvement with a lower risk of GI effects.
