LIGANDS FOR BRAIN CHOLINERGIC CHANNEL RECEPTORS - SYNTHESIS AND IN-VITRO CHARACTERIZATION OF NOVEL ISOXAZOLES AND ISOTHIAZOLES AS BIOISOSTERIC REPLACEMENTS FOR THE PYRIDINE RING IN NICOTINE
LIGANDS FOR BRAIN CHOLINERGIC CHANNEL RECEPTORS - SYNTHESIS AND IN-VITRO CHARACTERIZATION OF NOVEL ISOXAZOLES AND ISOTHIAZOLES AS BIOISOSTERIC REPLACEMENTS FOR THE PYRIDINE RING IN NICOTINE
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DOI：
10.1021/jm00052a005
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发表时间：
1994-12-23
影响因子：
7.3
通讯作者：
ARNERIC, SP
中科院分区：
文献类型：
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作者：
GARVEY, DS;WASICAK, JT;ARNERIC, SP
激活神经元烟碱型乙酰胆碱受体(NAChRs)的配体为阿尔茨海默病(AD)相关记忆丧失症状的姑息治疗提供了潜在的途径。基于这种方法，合成了一系列新的3，5-二取代异恶唑和异噻唑，并在体外评价了它们作为神经元nAChRs的胆碱能通道激活剂(ChCA)的作用。在大鼠全脑制剂中，许多3-取代5-(2-吡咯烷基)异恶唑具有与(S)-尼古丁(2a)相当的纳摩尔结合亲和力。然而，在测量大鼠纹状体制剂中诱发的[H-3]多巴胺释放的范例中，这些类似物的激动剂效力和效力与2a相比有所不同。在具有类似结合效力的化合物之间观察到的激动剂效力的差异可能是由于与神经元nAChRs不同亚型的配体相互作用的不同。
Ligands which activate neuronal nicotinic acetylcholine receptors (nAChRs) represent a potential approach for the palliative treatment for the symptoms of memory loss associated with Alzheimer's disease(AD). Based upon this approach, a series of novel 3,5-disubstituted isoxazoles and isothiazoles were prepared and evaluated in vitro as cholinergic channel activators (ChCAs) of neuronal nAChRs. Many of the 3-substituted 5-(2-pyrrolidinyl)isoxazoles were found to have nanomolar binding affinities comparable to (S)-nicotine (2a) in a preparation of whole rat brain. However, in a paradigm measuring the evoked release of [H-3]dopamine from a preparation of rat striatum, there were differences in the agonist potencies and efficacies of these analogues relative to 2a. The differences in agonist potency observed between compounds of comparable binding potency may be due to differences in ligand interactions with various subtypes of neuronal nAChRs.