呋喃并[3,2-b]吡啶类化合物对α7尼古丁乙酰胆碱受体负向变构调节作用的电生理学评价（英文）
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摘要
作者基于课题组先前得到的脱硫催化产物吡咯并[3,2-b]吡啶和呋喃并[3,2-b]吡啶类新型结构,通过双电极电压钳电生理技术记录表达人源α7乙酰胆碱受体通道的非洲爪蟾卵母细胞对合成的化合物进行了活性评价。在100μM的乙酰胆碱作用下,代表性呋喃并[3,2-b]吡啶化合物4f对α7烟碱型乙酰胆碱受体最大抑制率达87.8%和IC_(50)为5.51μM。化合物4f对α7烟碱型乙酰胆碱受体具有亚型选择性,是一类具有潜在研究价值的负向变构调节剂。
A series of 1H-pyrrolo[3,2-b]pyridine(3a–3f) and furo[3,2-b]pyridine derivatives(4a–4g) were evaluated on human α7 nicotinic acetylcholine receptors(nAChRs) using two-electrode voltage clamp(TEVC) recording. A representative 2-(2-methoxyphenyl)-furo[3,2-b]pyridine 4f as negative allosteric modulator(NAM) selectively inhibited alpha7 nAChR over α3β4, α4β2 nAChRs and 5-HT_(3A) receptor, with a potency of IC_(50) of 5.51 μM and a maximum inhibition rate of 87.8%. The preliminary analysis of structure-activity relationship(SAR) suggested that compound 4 f could serve as a basis for further discovery of potent and selective α7 nAChR NAMs.
A series of 1H-pyrrolo[3,2-b]pyridine(3a–3f) and furo[3,2-b]pyridine derivatives(4a–4g) were evaluated on human α7 nicotinic acetylcholine receptors(nAChRs) using two-electrode voltage clamp(TEVC) recording. A representative 2-(2-methoxyphenyl)-furo[3,2-b]pyridine 4f as negative allosteric modulator(NAM) selectively inhibited alpha7 nAChR over α3β4, α4β2 nAChRs and 5-HT_(3A) receptor, with a potency of IC_(50) of 5.51 μM and a maximum inhibition rate of 87.8%. The preliminary analysis of structure-activity relationship(SAR) suggested that compound 4 f could serve as a basis for further discovery of potent and selective α7 nAChR NAMs.
引文
[1]Chatzidaki,A.;Millar,N.S.Allosteric modulation of nicotinic acetylcholine receptors.Biochem.Pharmacol.2015,97,408-417.
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[14]Abdrakhmanova,G.R.;Blough,B.E.;Nesloney,C.;Navarro,H.A.;Damaj,M.I.;Carroll,F.I.In vitro and in vivo characterization of a novel negative allosteric modulator of neuronal n ACh Rs.Neuropharmacology.2010,59,511-517.
[15]Criado,M.;Balsera,B.;Mulet,J.;Sala,S.;Sala,F.;de la Torre-Martínez,R.;Fernández-Carvajal,A.;Ferrer-Montiel,A.;Moreno-Fernández,S.;Miguel,M.;Pérez de Vega,M.J.;González-Mu?iz,R.1,3-diphenylpropan-1-ones as allosteric modulators ofα7 n ACh receptors with analgesic and antioxidant properties.Future Med.Chem.2016,8,731-749.
[16]Sun,L.L.;Yang,T.Y.;Wei,N.N.;Lu,W.;Jiao,W.X.;Zhou,Q.Q.;Miao,Y.Z.;Gao,Q.;Wang,X.T.;Sun,Q.;Wang,K.W.Pharmacological characterization of JWX-A0108 as a novel type I positive allosteric modulator ofα7 n ACh R that can reverse acoustic gating deficits in a mouse prepulse inhibition model.Acta Pharmacol.Sin.2018,DOI:org/10.1038/s41401-018-0163-y.
[17](a)Li,Y.H.;Sun,L.L.;Yang,T.Y.;Jiao,W.X.;Tang,J.S.;Huang,X.M.;Huang,Z.Z.;Meng,Y.;Luo,L.C.;Wang,X.T.;Bian,X.L.;Zhang,F.;Wang,K.W.;Sun,Q.Design and synthesis of novel positive allosteric modulators of alpha7 nicotinic acetylcholine receptors with the ability to rescue auditory gating deficit in mice.J.Med.Chem.2019,62,159-173.(b)Meng,Y.;Zou,W.X.;Huang,Z.Z.;Wang,X.T.;Jiao,W.X.;Xie,W.J.;Bian,X.L.;Wang,K.W.;Sun,Q.Development of palladium-catalyzed Suzuki carbonylation reaction without external ligand and its application in modification of novel series ofα7 n ACh R PAMs.J.Chin.Pharm.Sci.2018,27,460-468.
[18]Huang,Z.Z;Wang,X.T.;Meng,M;Li,X.;Xiao,H.R.;Bian,X.L.;Wang,K.W.;Sun,Q.The design,synthesis andα7 nicotinic acetylcholine receptors positive allosteric modulative evaluation of 3H-quinazolin-4-one derivatives.J.Chin.Pharm.Sci.2018,27,540-552.
[19]Zou,W.X.;Huang,Z.Z.;Jiang,K.;Wu,Y.;Xue,Y.Q.;Suzenet,F.;Sun,Q.;Guillaumet,G.Chelation-assisted C-S activation/cascade heteroannulation of pyridine-2-thione derivatives in Pd-catalyzed cross-coupling reaction with alkynes.Tetrahedron.2017,73,5485-5492.
[20]Tang,J.S.;Xie,B.X.;Bian,X.L.;Xue,Y.;Wei,N.N.;Zhou,J.H.;Hao,Y.C.;Li,G;Zhang,L.R.;Wang,K.W.Identification and in vitro pharmacological characterization of a novel and selectiveα7 nicotinic acetylcholine receptor agonist,Br-IQ17B.Acta Pharmacol.Sin.2015,36,800-812.
[2]Dineley,K.T.;Pandya,A.A.;Yakel,J.L.Nicotinic ACh receptors as therapeutic targets in CNS disorders.Trends Pharmacol.Sci.2015,36,96-108.
[3]Wallace,T.L.;Porter,R.H.Targeting the nicotinic alpha7acetylcholine receptor to enhance cognition in disease.Biochem.Pharmacol.2011,82,891-903.
[4]Echeverria,V.;Yarkov,A.;Aliev,G.Positive modulators of theα7 nicotinic receptor against neuroinflammation and cognitive impairment in Alzheimer's disease.Prog.Neurobiol.2016,144,142-157.
[5]Wallace,T.L.;Bertrand,D.Alpha7 neuronal nicotinic receptors as a drug target in schizophrenia.Expert Opin.Ther.Targets.2013,17,139-155.
[6]Yang,T.;Xiao,T.;Sun,Q.;Wang,K.W.The current agonists and positive allosteric modulators ofα7 n ACh Rfor CNS indications in clinical trials.Acta Pharm.Sin.B.2017,7,611-622.
[7]Pandya,A.A.;Yakel,J.L.Effects of neuronal nicotinic acetylcholine receptor allosteric modulators in animal behavior studies.Biochem.Pharmacol.2013,86,1054-1062.
[8]Jones,C.K.;Byun,N.;Bubser,M.Muscarinic and nicotinic acetylcholine receptor agonists and allosteric modulators for the treatment of schizophrenia.Neuropsychopharmacology.2012,37,16-42.
[9]Williams,D.K.;Wang,J.Y.;Papke,R.L.Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics:Advantages and limitations.Biochem.Pharmacol.2011,82,915-930.
[10]Corradi,J.;Bouzat,C.Understanding the bases of function and modulation ofα7 nicotinic receptors:implications for drug discovery.Mol.Pharmacol.2016,90,288-299.
[11]Bertrand,D.;Gopalakrishnan,M.Allosteric modulation of nicotinic acetylcholine receptors.Biochem.Pharmacol.2007,74,1155-1163.
[12]Collins,T.;Young,G.T.;Millar,N.S.Competitive binding at a nicotinic receptor transmembrane site of twoα7-selective positive allosteric modulators with differing effects on agonist-evoked desensitization.Neuropharmacology.2011,61,1306-1313.
[13]Criado,M.;Mulet,J.;Sala,F.;Sala,S.;Colmena,I.;Gandía,L.;Bautista-Aguilera,O.M.;Samadi,A.;Chioua,M.;Marco-Contelles,J.N-Benzylpiperidine derivatives asα7 nicotinic receptor antagonists.ACSChem.Neurosci.2016,7,1157-1165.
[14]Abdrakhmanova,G.R.;Blough,B.E.;Nesloney,C.;Navarro,H.A.;Damaj,M.I.;Carroll,F.I.In vitro and in vivo characterization of a novel negative allosteric modulator of neuronal n ACh Rs.Neuropharmacology.2010,59,511-517.
[15]Criado,M.;Balsera,B.;Mulet,J.;Sala,S.;Sala,F.;de la Torre-Martínez,R.;Fernández-Carvajal,A.;Ferrer-Montiel,A.;Moreno-Fernández,S.;Miguel,M.;Pérez de Vega,M.J.;González-Mu?iz,R.1,3-diphenylpropan-1-ones as allosteric modulators ofα7 n ACh receptors with analgesic and antioxidant properties.Future Med.Chem.2016,8,731-749.
[16]Sun,L.L.;Yang,T.Y.;Wei,N.N.;Lu,W.;Jiao,W.X.;Zhou,Q.Q.;Miao,Y.Z.;Gao,Q.;Wang,X.T.;Sun,Q.;Wang,K.W.Pharmacological characterization of JWX-A0108 as a novel type I positive allosteric modulator ofα7 n ACh R that can reverse acoustic gating deficits in a mouse prepulse inhibition model.Acta Pharmacol.Sin.2018,DOI:org/10.1038/s41401-018-0163-y.
[17](a)Li,Y.H.;Sun,L.L.;Yang,T.Y.;Jiao,W.X.;Tang,J.S.;Huang,X.M.;Huang,Z.Z.;Meng,Y.;Luo,L.C.;Wang,X.T.;Bian,X.L.;Zhang,F.;Wang,K.W.;Sun,Q.Design and synthesis of novel positive allosteric modulators of alpha7 nicotinic acetylcholine receptors with the ability to rescue auditory gating deficit in mice.J.Med.Chem.2019,62,159-173.(b)Meng,Y.;Zou,W.X.;Huang,Z.Z.;Wang,X.T.;Jiao,W.X.;Xie,W.J.;Bian,X.L.;Wang,K.W.;Sun,Q.Development of palladium-catalyzed Suzuki carbonylation reaction without external ligand and its application in modification of novel series ofα7 n ACh R PAMs.J.Chin.Pharm.Sci.2018,27,460-468.
[18]Huang,Z.Z;Wang,X.T.;Meng,M;Li,X.;Xiao,H.R.;Bian,X.L.;Wang,K.W.;Sun,Q.The design,synthesis andα7 nicotinic acetylcholine receptors positive allosteric modulative evaluation of 3H-quinazolin-4-one derivatives.J.Chin.Pharm.Sci.2018,27,540-552.
[19]Zou,W.X.;Huang,Z.Z.;Jiang,K.;Wu,Y.;Xue,Y.Q.;Suzenet,F.;Sun,Q.;Guillaumet,G.Chelation-assisted C-S activation/cascade heteroannulation of pyridine-2-thione derivatives in Pd-catalyzed cross-coupling reaction with alkynes.Tetrahedron.2017,73,5485-5492.
[20]Tang,J.S.;Xie,B.X.;Bian,X.L.;Xue,Y.;Wei,N.N.;Zhou,J.H.;Hao,Y.C.;Li,G;Zhang,L.R.;Wang,K.W.Identification and in vitro pharmacological characterization of a novel and selectiveα7 nicotinic acetylcholine receptor agonist,Br-IQ17B.Acta Pharmacol.Sin.2015,36,800-812.
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