Abstract
Compounds with excellent receptor engagement displaying α2-AR antagonist activity are useful not only for therapeutic purposes (e.g. antidepressants), but also to help in the crystallization of this particular GPCR. Therefore, based on our broad experience in the topic, we have prepared eighteen di-aryl (phenyl and/or pyridin-2-yl) mono- or di-substituted guanidines and 2-aminoimidazolines. The invitro α2-AR binding affinity experiments in human brain tissue showed the advantage of a 2-aminoimidazolinium cation, a di-arylmethylene core, a conformationally locked pyridin-2-yl-guanidine and a di-substituted guanidinium to achieve good α2-AR engagement. After different invitro [35S]GTPγS binding experiments in human prefrontal cortex tissue, it was possible to identify that compounds 7a, 7b and 7c were α2-AR partial agonist, whereas 8h was a potent α2-AR antagonist. Docking and MD studies with a model of α2A-AR and two crystal structures suggest that antagonism is achieved by compounds carrying a di-substituted guanidine which substituent occupy a pocket adjacent to TM5 without engaging S2005.42 or S2045.46, and a mono-substituted cationic group, which favorably interacts with E942.65.
Highlights
In recent years there has been a huge advancement in understanding neural regions and circuits implicated in stress responses of affective disorders such as depression [1e3], there is still limited novel treatments to show for it
We present the synthesis of a series of di-arylmethane guanidines and 2-aminoimidazolines emanating from the promising pharmacological profiles of initial derivatives as well as the pharmacological evaluation of their in vitro a2-AR binding affinity and activity in human PFC brain tissue
In order to probe if flexibility between the aryl rings is important, compounds with a methylene linker as in ‘hit’ 1 (7a-c, Fig. 2) and an ethylene linker (7d-f, Fig. 2) were investigated, since good a2-AR antagonist activity has been obtained for previously prepared ethylene linked di-phenyl molecules [11]
Summary
In recent years there has been a huge advancement in understanding neural regions and circuits implicated in stress responses of affective disorders such as depression [1e3], there is still limited novel treatments to show for it. Therapeutic approach to date [4], and it is accepted that this alteration in chemical concentration indirectly induces the gradual strengthening of synapses (neuroplasticity) and synthesis of new neurons (neurogenesis) over the course of treatment to elicit the behavioural antidepressant response [5]. Noradrenergic transmission plays a central role in the mediation of stress where alterations in its signalling as well as changes in physical features of its plasticity are heavily implicated in stressrelated disorders [6]. Clinical a2-AR antagonists have shown to have faster behavioural antidepressant responses than conventional antidepressants alone, which are thought to be due to a combination of their effects on noradrenaline transmission, as well as influencing key responses involved in neuroplasticity and neurogenesis.
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