Deoxamuscaroneoxime derivatives as useful muscarinic agonists to explore the muscarinic subsite: Demox, a modulator of orthosteric and allosteric sites at cardiac muscarinic M2 receptors
- 作者：Angeli ; Piero ; Marucci ; Gabriella ; Buccioni ; Michela ; Piergentili ; Alessandro ; Giannella ; Mario ; et. al.
- 关键词：Muscarinic subsite ; Deoxamuscaroneoxime derivatives ; Orthosteric and allosteric sites ; Cardiac M2 receptors
- 刊名：Life Sciences
- 出版年：2002
- 期刊代码：62_00243205
- 类别：imm
- 出版时间：February 8, 2002
- 卷：70
- 期：12
- 页码：1427-1446
- 文件大小：437 K
摘要
A series of muscarinic agonists, straight chained, branched, cyclic alkyl and aromatic derivatives of the oxime 1 (demox) was designed with the aim of investigating their activity on muscarinic receptor subtypes. Effects on M1 receptor were assessed functionally by a microphysiometer apparatus, while M2, M3, and M4 receptor potency and affinity were studied on isolated preparations of guinea pig heart, ileum, and lung, respectively. The results suggest that the substitution of a hydrogen with a long side-chain or bulky group generally induces a decrease in potency at M1 and M3 subtypes, while a general increase in this parameter is obtained at M2 subtype. Among the agonists 2–18, compound 4 behaves as a full agonist with a preference for M3 subtype. Moreover, compound 12 is inactive at M1 and M4 receptors while it displays a full agonist activity at M2 and M3 subtypes. Since demox displays a variable response on cardiac M2 receptors regulating heart force, an in-depth inquiry of the functional behaviour of this compound was carried out at M2 receptors. In presence of 10−11 and 10−10 M demox, the binding of [3H]-NMS was increased by 
30%as a consequence of an increase of the association of [3H]-NMS to membranes; this effect was not observed in presence of a higher concentration of [3H]-NMS. Higher concentrations of demox decreased the binding of [3H]-NMS to heart atrial membranes but significantly retarded the dissociation of this radioligand. Our results suggest that demox may interact with orthosteric and allosteric sites of atrial M2 muscarinic receptor.
30%as a consequence of an increase of the association of [3H]-NMS to membranes; this effect was not observed in presence of a higher concentration of [3H]-NMS. Higher concentrations of demox decreased the binding of [3H]-NMS to heart atrial membranes but significantly retarded the dissociation of this radioligand. Our results suggest that demox may interact with orthosteric and allosteric sites of atrial M2 muscarinic receptor.