Cooperative interactions at m2 muscarinic acetylcholine receptors: Structure/activity relationships in stepwise shortened bispyridinium- and bis(ammonio)alkane-type allosteric modulators
Küçük Resim Yok
Tarih
2003
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Erişim Hakkı
info:eu-repo/semantics/closedAccess
Özet
Muscarinic M2-receptors allow for divergent modes of allosteric action, depending on the structure of the allosteric modulator. Phthalimido-substituted bis(ammonio)alkane-type modulators belong to the common mode allosteric agents, whereas a physicochemically closely related bispyridinium-oxime with dichlorobenzyl-substituents at both ends is an atypical agent. Here, we compared the actions of stepwise shortened compounds composed of the phthalimido moiety and middle chains of either the bispyridinium- or the bis(ammonio)alkane-type. Allosteric interactions were measured in pig M2 receptors with the orthosteric probe [3H]N-methylscopolamine ([3H]NMS) to label the acetylcholine binding site of the receptors. Dissociation and equilibrium binding experiments revealed parallel structure/activity-relationships in both series of compounds with regard to the cooperativity of interaction with [3H]NMS and to the underlying binding affinities in radioligand-occupied and free receptors. In conclusion, the findings are in line with the hypothesis that the phthalimido-moiety, but not the middle chain, is pivotal for the topology of interaction with the M2-receptor protein.
Açıklama
Anahtar Kelimeler
Allosteric interactions, Cooperativity, Muscarinic receptors, Structure/activity relationships
Kaynak
Neurochemical Research
WoS Q Değeri
Scopus Q Değeri
Q1
Cilt
28
Sayı
03.Apr
