Functional selectivity – chance for better and safer drugs?

Abstract

Purpose: The article reviews the current state of knowledge about functional selectivity (biased agonism) at G protein-coupled receptors (GPCRs), with a particular focus on serotonin 5-HT 1A receptors. Views: Recently, functional selectivity has been one of the fastest growing topics in GPCRs pharmacology. Research on this phenomenon allowed identification of signal transduction pathways which can be preferentially targeted to achieve improved therapeutic effects or, conversely, which are associated with adverse effects. Oliceridine, a phase III clinical candidate for treatment of pain, is an example of a functionally selective ligand of µ-opioid receptors that preferentially activates signal transduction via G proteins rather than β-arrestin. Biased agonism, or the ability to preferentially activate specific signalling pathways, has been identified for many therapeutically important GPCRs, such as µ-opioid receptors, α 1 -and β 2 -adrenoceptors, dopamine D 2L and D 1 receptors, angiotensin 1A receptor, as well as 5-HT 2 and 5-HT 1A serotonin receptors. The recently discovered compounds F15599 and F13714 have been identified as functionally and regionally selective ligands of 5-HT 1A receptors. These compounds constitute a new generation of pharmacological tools with high therapeutic potential, which is currently being investigated for the treatment of disorders including Parkinson's disease, depression and Rett syndrome. Conclusions: Functional selectivity (biased agonism) enables separation of the therapeutic effect from the adverse effects, so far considered to be intrinsically linked to the mechanism of action, by preferentially targeting signal transduction pathways associated with beneficial effects. It may therefore offer new opportunities for improved development of more effective and safer drugs. Key words: functional selectivity, biased agonism, 5-HT 1A receptor, F15599, F13714. StreszczenieCel: W pracy przedstawiono aktualny stan wiedzy na temat zjawiska selektywności funkcjonalnej (stronniczego agonizmu) w farmakologii receptorów sprzężonych z białkiem G (G protein-coupled receptors -GPCRs), ze szczególnym uwzględnieniem receptorów serotoninowych typu 1A. Poglądy: W ostatnich latach selektywność funkcjonalna stała się jednym z najszybciej rozwijających się tematów w farmakologii GPCRs. Badania nad tym zjawiskiem umożliwiają identyfikację szlaków transdukcji sygnału, które są preferowane dla efektu terapeutycznego lub związane z efektami niepożądanymi danego receptora. Przykładem może być olicerydyna, agonista receptorów opioidowych, selektywny funkcjonalnie wobec ścieżki przekazywania sygnału przez białko G względem β-arestyny, tj. nowy kandydat na lek przeciwbólowy. Selektywność funkcjonalna, nazywana inaczej stronniczym agonizmem, czyli zdolność do preferencyjnej aktywacji wybranej ścieżki sygnałowej, została zidentyfikowana w obrębie całej gamy ważnych terapeutycznie celów z rodziny GPCRs, m.in. receptorów μ-opioidowych, α 1 -i β 2 -adrenergicznych, dopaminowych D 2L i D 1 , angiotensynowy...

The role of aryl-topology in balancing between selective and dual 5-HT7R/5-HT1Aactions of 3,5-substituted hydantoins

“…The designed new derivatives (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) were obtained based on the previously optimized three-step pathway 19 starting from Bucherer-Bergs reaction, which led to the hydantoin system formation, followed by N-alkylation with epichlorhydrin and solvent-free microwave-assisted condensation with simultaneous epoxide opening (Scheme 1). Compounds 15-17 were synthesized in two steps using commercially available 5,5dimethylhydantoin as the starting material.…”

“…However, this decrease is not as severe as in the case of the presence of two phenyl rings (5,5-diphenylhydantoin, 189-fold decrease with respect to 1). 19 Interestingly, the exchange of the phenyl ring at position 5 of hydantoin to 1-or 2-naphthyl was beneficial and did not disrupt the high 5-HT 7 R affinity, making compounds 10, 11, 13 and 14 the most active in the entire series (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). For the naphthyl derivatives with the (2-methoxyphenyl)piperazine fragment (10 and 13), the 5-HT 7 R affinity was almost identical as that for the 1st generation lead 1.…”

“…Targeting receptor 5-HT 7 , the youngest member of the serotoninergic system, [1][2][3] seems to be a promising approach in terms of treatment of CNS disorders, such as depression 4 and schizophrenia-like cognitive impairments. 5 However, when considering the design of 5-HT 7 R ligands, the same dilemma still remains, viz., whether selective 6,7 or multitargeted therapy 8,9 is the better solution for CNS patients. The selective mechanism of action targeting only the desired protein gives hope for decreased probability of side-effects manifestation caused by interactions with off-targets.…”

“…By going deeper according to the functional selectivity approach, it is possible to activate not only the chosen biological target, but also the specific signal transduction pathway. 6 It is also worth mentioning that only one selective 5-HT 7 R ligand, compound JNJ-18038683, has been studied in clinical trials; however, unfortunately, its antidepressant action has not been proved due to the lack of sensitivity of performed studies. 7 Thus, searching a potent and selective 5-HT 7 R ligand seems to be a significant direction in order to verify potential advantages and disadvantages of selective therapy.…”

The selective 5-HT1A receptor biased agonists, F15599 and F13714, show antidepressant-like properties after a single administration in the mouse model of unpredictable chronic mild stress

“…G-protein-coupled receptors (GPCRs) exist in many active conformations and coupled to various intracellular transducers (Wootten et al 2018;Sałaciak and Pytka 2021). According to many studies, different ligands that bind to the same receptor may stabilize it in distinct conformations that preferentially activate specific signaling pathways, without affecting, or potentially even blocking, other transduction mechanisms (Śniecikowska et al 2017;Wootten et al 2018). This well-established paradigm is called functional selectivity or biased agonism.…”