Abstract
The complex pathophysiology of depression, together with the limits of currently available antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Numerous findings suggest that pharmacological blockade of α2-adrenoceptor might be beneficial for the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in certain brain areas. Moreover, the antidepressant properties of 5-HT7 receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α2-adrenoceptors and 5-HT7 receptors, we designed a small series of arylsulfonamide derivatives of (dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound 8 behaved as a potent α2A/5-HT7 receptor antagonist and displayed moderate-to-high selectivity over α1-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound 8 improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine.
Highlights
Depressive disorder is a common and disabling illness characterized by the presence of behavioral and emotional symptoms [1]
In view of the findings that the modulation of noradrenergic/serotonin transmissions by targeting α2-AR and the blockade of 5-HT7R are involved in behavioral changes responsible for antidepressant-like effects observed in preclinical models [7,10,41], selected compounds 6, 8 and 13 were assessed for their potential antidepressant properties in the forced swim test using Albino Swiss mice
Based on the finding that concurrent blockade of α2-AR and 5-HT7R might be beneficial in the treatment of depressive disorders, we elaborated a medicinal mechanochemical approach to provide a limited series of arylsulfonamides ofethyl piperidines as dual acting α2/5-HT7R antagonists
Summary
Depressive disorder is a common and disabling illness characterized by the presence of behavioral and emotional symptoms (i.e., sleep disturbances, low self-esteem, sadness as well as suicidal ideation) [1]. Different pharmacotherapeutic options are available (e.g., selective serotonin reuptake inhibitors SSRIs–; serotonin/noradrenaline reuptake inhibitors SNRIs; monoamine receptors modulators), the treatment of depressive disorders is still limited. Available antidepressants display a delay of therapeutic action, which lasts up to a few weeks in some patients after numerous antidepressant drugs, and numerous unacceptable side effects [2]. TThhee 55--HHTT77 rreecceeppttoorr ((55--HHTT77RR)) rreepprreesseennttss tthhee llaatteesstt aaddddiittiioonn ttoo aa ssuubbffaammiillyy ooff sseerroottoonniinn GGPPCCRRss [[88]]. TThhee iimmppaacctt ooff tthhee aapppplliieedd mmooddiifificcaattiioonnssoonntthheeaafffifinniittyyffoorrαα22--AARR aanndd55--HHTT77RR wwaass fifirrsstt aasssseesssseedd iinn vviittrroo iinn rraaddiioolliiggaanndd bbiinnddiinngg ssttuuddiieess. TThhee sseelleeccttiivviittyy ooff tthhee mmoosstt pprroommiissiinngg ddeerriivvaattiivveess oovveerr ssttrruuccttuurraallllyy rreellaatteeddooffff--ttaarrggeettGGPPCCRRss(α(α1-1A-ARR,,55-H-HTT1A1ARR,,55--HHTT22AARR,, 55--HHTT66RR aanndd DD22RR)) wwaass investigated, followed by a determination of their antagonistic properties at α2A-AR and 5-HT7R in cellular assays. The selected derivatives improved performance of mice in the forced swim test. The selected derivatives improved performan3coefo19f mice in the forced swim test
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