Abstract
Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT1A receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential “signaling fingerprints” that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of “serotonergic syndrome”. Both compounds showed promising developability properties. The presented 5-HT1A receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.
Highlights
Serotonin 5-HT1A receptors exert a major influence on central nervous system (CNS) functions such as mood, pain, and movement and were identified several decades ago,1,2 it is notable that there are still no selective 5-HT1A receptor agonists approved for therapeutic intervention
5-HT1A autoreceptors is associated with prodepressive effects, notably by inhibiting the release of serotonin in terminal regions.7,8. These contrasting effects have long been the object of discussion in the search for more efficacious antidepressants and suggest that indiscriminate activation of multiple 5-HT1A receptor subpopulations may limit the therapeutic efficacy of 5-HT1A receptor agonists or elicit unacceptable side effects
Our previous work investigated the structure−activity relationship (SAR) and structure functional activity relationships (SFARs) of novel analogues designed based on the structure of 1.13 In that study, we identified a new, patentable, and synthetically versatile chemotype of selective 5-HT1A receptor-biased agonists that preferentially activate ERK1/2 phosphorylation in vitro and show potent antidepressant-like properties in vivo
Summary
Serotonin 5-HT1A receptors exert a major influence on central nervous system (CNS) functions such as mood, pain, and movement and were identified several decades ago, it is notable that there are still no selective 5-HT1A receptor agonists approved for therapeutic intervention. There are, commercialized drugs that exhibit some agonist properties at 5-HT1A receptors, including the anxiolytic buspirone (Buspar), the antidepressant vortioxetine (Brintellix), the antipsychotic aripiprazole (Abilify), and the antiparkinsonian bromocriptine (Parlodel).− all of these compounds interact with other targets, including other monoamine receptors or transporters, and they only partially activate 5-HT1A receptors (i.e., they function as “partial agonists”). Such compounds do not discriminate between subpopulations of 5-HT1A receptors which are expressed in different brain regions and that mediate various, sometimes opposing, physiological and behavioral responses. Recent advances have shown that it is possible to selectively target 5-HT1A receptors in desired brain areas, such as the cortex or brain stem, leading to significantly improved and promising therapeutic-like outcomes
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