A series of new 6-substituted 3 H-quinazolin-4-ones（3 a-3 d） were designed, synthesized and evaluated as the type I positive allosteric modulators（PAMs） of human α7 n ACh R expressed in Xenopus ooctyes by two-ele...A series of new 6-substituted 3 H-quinazolin-4-ones（3 a-3 d） were designed, synthesized and evaluated as the type I positive allosteric modulators（PAMs） of human α7 n ACh R expressed in Xenopus ooctyes by two-electrode voltage clamp. However, no compound showed a better efficacious PAM than lead compound 2 in the presence of acetylcholine（100 μM）. The structure-activity relationship（SAR） analysis suggested that thiazolo[4,5-d]pyrimidin-7（6 H）-one was the key biological skeleton.展开更多
A series of 1H-pyrrolo[3,2-b]pyridine(3a-3f)and furo[3,2-b]pyridine derivatives(4a-4g)were evaluated on humanα7 nicotinic acetylcholine receptors(nAChRs)using two-electrode voltage clamp(TEVC)recording.A representati...A series of 1H-pyrrolo[3,2-b]pyridine(3a-3f)and furo[3,2-b]pyridine derivatives(4a-4g)were evaluated on humanα7 nicotinic acetylcholine receptors(nAChRs)using two-electrode voltage clamp(TEVC)recording.A representative 2-(2-methoxy-phenyl)-furo[3,2-b]pyridine 4f as negative allosteric modulator(NAM)selectively inhibited alpha7 nAChR overα3β4,α4β2 nAChRs and 5-HT_(3A) receptor,with a potency of IC_(50) of 5.51μM and a maximum inhibition rate of 87.8%.The preliminary analysis of structure-activity relationship(SAR)suggested that compound 4f could serve as a basis for further discovery of potent and selectiveα7 nAChR NAMs.展开更多
A series of 2-arylamino-1,3,5-triazine derivatives(4a–4g),which were designed and synthesized via Sonogashira coupling reaction,were evaluated using two-electrode voltage clamp(TEVC)recordings of humanα7 nAChR expre...A series of 2-arylamino-1,3,5-triazine derivatives(4a–4g),which were designed and synthesized via Sonogashira coupling reaction,were evaluated using two-electrode voltage clamp(TEVC)recordings of humanα7 nAChR expressed in Xenopus ooctyes.Compound 4g as a positive allosteric modulator(PAM)showed better efficacy than lead compound 3(HZZ-A-11)with an EC50 value of 1.23±0.41μM.Further pharmacological evaluation of compound 4g might lead to the developmental potential for therapy of cognitive deficits commonly shared by neuropsychiatric disorders,such as schizophrenia and Alzheimer’s disease.展开更多
Palladium-catalyzed Suzuki carbonylation with CHCl3 as carbonylative reagent was realized without external ligands. Different substituted benzophenones were explored via the coupling reaction of aryl iodides, arylboro...Palladium-catalyzed Suzuki carbonylation with CHCl3 as carbonylative reagent was realized without external ligands. Different substituted benzophenones were explored via the coupling reaction of aryl iodides, arylboronic acids and CHCl3 as a CO surrogate in moderate to good yields. This method was also successfully applied to the structure modification of α7 nicotinic acetylcholine receptor positive allosteric modulators（α7 nAChR PAMs） based on the preliminary structure-activity relationship.展开更多
Mutations（dots in upper panel）of voltage-gated KCNQ channels（central panel）lead to neuronal hyper-excitability（from left panel to right panel）and epilepsy.Suppression of neuronal hyper-excitability（from right p...Mutations（dots in upper panel）of voltage-gated KCNQ channels（central panel）lead to neuronal hyper-excitability（from left panel to right panel）and epilepsy.Suppression of neuronal hyper-excitability（from right panel to left panel）by KCNQ2/3 channels opener retigabine（lower panel）serves the basis for treatment of epilepsy.M-type potassium current（IM）was initially isolated from sympathetic neurons in 1980 and named as it was inhibited展开更多
基金National Natural Science Foundation of China(NSFC,Grant No.21572011)Ministry of Science and Technology of China(Grant No.2013CB531302)
文摘A series of new 6-substituted 3 H-quinazolin-4-ones（3 a-3 d） were designed, synthesized and evaluated as the type I positive allosteric modulators（PAMs） of human α7 n ACh R expressed in Xenopus ooctyes by two-electrode voltage clamp. However, no compound showed a better efficacious PAM than lead compound 2 in the presence of acetylcholine（100 μM）. The structure-activity relationship（SAR） analysis suggested that thiazolo[4,5-d]pyrimidin-7（6 H）-one was the key biological skeleton.
基金National Natural Science Foundation(Grant No.21572011,81537410)Ministry of Science and Technology(Grant No.2014ZX09507003-006-004)
文摘A series of 1H-pyrrolo[3,2-b]pyridine(3a-3f)and furo[3,2-b]pyridine derivatives(4a-4g)were evaluated on humanα7 nicotinic acetylcholine receptors(nAChRs)using two-electrode voltage clamp(TEVC)recording.A representative 2-(2-methoxy-phenyl)-furo[3,2-b]pyridine 4f as negative allosteric modulator(NAM)selectively inhibited alpha7 nAChR overα3β4,α4β2 nAChRs and 5-HT_(3A) receptor,with a potency of IC_(50) of 5.51μM and a maximum inhibition rate of 87.8%.The preliminary analysis of structure-activity relationship(SAR)suggested that compound 4f could serve as a basis for further discovery of potent and selectiveα7 nAChR NAMs.
基金National Natural Science Foundation of China aw arded to Q.Sun(NSFC,Grant No.81973169,21572011)and K.W.Wang(NSFC,Grant No.81537410)the Ministry of Science and Technology of China to K.W.Wang(Grant No.2014ZX09507003-006-004)。
文摘A series of 2-arylamino-1,3,5-triazine derivatives(4a–4g),which were designed and synthesized via Sonogashira coupling reaction,were evaluated using two-electrode voltage clamp(TEVC)recordings of humanα7 nAChR expressed in Xenopus ooctyes.Compound 4g as a positive allosteric modulator(PAM)showed better efficacy than lead compound 3(HZZ-A-11)with an EC50 value of 1.23±0.41μM.Further pharmacological evaluation of compound 4g might lead to the developmental potential for therapy of cognitive deficits commonly shared by neuropsychiatric disorders,such as schizophrenia and Alzheimer’s disease.
基金The National Natural Science Foundation of China(Grant No.21572011 and 21272009)
文摘Palladium-catalyzed Suzuki carbonylation with CHCl3 as carbonylative reagent was realized without external ligands. Different substituted benzophenones were explored via the coupling reaction of aryl iodides, arylboronic acids and CHCl3 as a CO surrogate in moderate to good yields. This method was also successfully applied to the structure modification of α7 nicotinic acetylcholine receptor positive allosteric modulators（α7 nAChR PAMs） based on the preliminary structure-activity relationship.
文摘Mutations（dots in upper panel）of voltage-gated KCNQ channels（central panel）lead to neuronal hyper-excitability（from left panel to right panel）and epilepsy.Suppression of neuronal hyper-excitability（from right panel to left panel）by KCNQ2/3 channels opener retigabine（lower panel）serves the basis for treatment of epilepsy.M-type potassium current（IM）was initially isolated from sympathetic neurons in 1980 and named as it was inhibited
