关于吡唑并[1',5':1,6]嘧啶并[4,5-d]哒嗪-4(3H)-酮作为强效和选择性人A1腺苷受体拮抗剂的进一步研究。

Further studies on pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones as potent and selective human A1 adenosine receptor antagonists.

作者信息

Giovannoni Maria Paola, Ciciani Giovanna, Cilibrizzi Agostino, Crocetti Letizia, Daniele Simona, Di Cesare Mannelli Lorenzo, Ghelardini Carla, Giacomelli Chiara, Guerrini Gabriella, Martini Claudia, Trincavelli Maria Letizia, Vergelli Claudia

机构信息

Dipartimento NEUROFARBA, Sezione Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.

出版信息

Eur J Med Chem. 2015 Jan 7;89:32-41. doi: 10.1016/j.ejmech.2014.10.020. Epub 2014 Oct 12.

DOI:10.1016/j.ejmech.2014.10.020

PMID:25462223

Abstract

A new series of pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones was synthesized and tested in radioligand binding assays on human A1, A2A and A3 adenosine receptors. Most of the compounds showed high selectivity of action towards A1 receptor and high affinity with Ki values in the low nanomolar range. The pharmacological profile of the most active molecules towards A1 adenosine receptors was evaluated in cAMP functional assay. Compounds demonstrated their ability to completely counteract the effect of the agonist NECA, thus demonstrating their antagonist profile. Moreover, the most interesting compound, tested in the mouse passive avoidance, exhibited an antiamnesic effect at the doses of 10 and 30 mg/kg.

摘要

合成了一系列新的吡唑并[1',5':1,6]嘧啶并[4,5-d]哒嗪-4(3H)-酮，并在人A1、A2A和A3腺苷受体的放射性配体结合试验中进行了测试。大多数化合物对A1受体表现出高选择性作用，且亲和力高，其Ki值在低纳摩尔范围内。在cAMP功能试验中评估了最具活性的分子对A1腺苷受体的药理作用特征。化合物显示出完全抵消激动剂NECA作用的能力，从而证明了它们的拮抗剂特征。此外，在小鼠被动回避试验中测试的最有趣的化合物，在10和30mg/kg剂量下表现出抗遗忘作用。