New spirohydantoin derivatives : synthesis, pharmacological evaluation and molecular modeling study

A series of new arylpiperazinylpropyl derivatives of 8/6-phenyl-1,3-diazaspiro[4.5]decan-2,4-dione and spiro[imidazolidine-4,1í-indene/naphthalene]-2,5-dione was synthesized and their affinity was evaluated toward serotonin 5-HT1A, 5-HT2A, 5-HT7 receptors, dopaminergic D2, D3 receptors, adrenergic α1 receptors, and serotonin transporter (SERT). The highest affinity for serotonin 5-HT1A/2A/7 receptors was found for compounds containing a tetralin or indane moiety in the imide part. Among these, two compounds (19, 20) were selected for further pharmacological in vivo studies. A binding mode of representative molecule 19, which behaved as a 5-HT1A agonist and weak 5-HT7 antagonist in the site of 5-HT1A/7, was also analyzed in computationa studies. Moreover, two highly selective (9 and 11) 5-HT2A receptor antagonists were obtained

Activity of Serotonin 5‑HT_1A Receptor Biased Agonists in Rat: Anxiolytic and Antidepressant-like properties

Although serotonin 5-HT_1A receptors constitute attractive therapeutic targets, there is a lack of potential clinical candidates that have a high degree of selectivity and full agonist efficacy. Recently, novel 5-HT_1A receptor “biased agonists” F15599 (also known as NLX-101) and F13714 have been reported that exhibit distinctive properties for in vitro signaling, neurochemical, electrophysiological effects, and in brain imaging. The present study characterized their effects in rat models of anxiety (elevated plus-maze, EPM, and Vogel tests), in depressive-like behavior (forced swim test), and on the induction of the three serotonergic behaviors (forepaw treading, flat body posture, and lower lip retraction). The prototypical 5-HT_1A receptor ligands (±)­8-OH-DPAT and buspirone were tested as comparators. In the elevated plus-maze, F15599, F13714, and (±)­8-OH-DPAT dose-dependently increased the amount and percentage of time spent in the open arms with minimal effective doses (MED) of 5 mg/kg p.o., 2.5 mg/kg p.o. and 1.25 mg/kg s.c., respectively. The effects of the three agonists were abolished by pretreatment with the selective 5-HT_1A receptor antagonist, WAY100635 (0.63 mg/kg s.c.). Buspirone did not show significant activity in the EPM. In contrast, in the Vogel test only buspirone was active, significantly increasing the number of licks and shocks accepted (active dose: 1.25 mg/kg s.c.). However, WAY100635 failed to reverse the effects of buspirone in this test, suggesting that they were not 5-HT_1A receptor-mediated. In the forced swim test, F15599, F13714, and (±)­8-OH-DPAT were potently active, abolishing immobility (MED: 0.63 mg/kg p.o., 0.63 mg/kg p.o. and 0.16 mg/kg s.c., respectively). Buspirone was not active. In measures of serotonergic behavior, F13714 and (±)­8-OH-DPAT robustly elicited all three signs of serotonergic behaviors, whereas F15599 and buspirone elicited only lower-lip retraction. Taken together, these observations highlight the distinct profiles of activity of 5-HT_1A agonists and suggest that the novel biased agonist F15599 combines pronounced activity in a test of anxiety (elevated plus-maze) with potent antidepressant-like effects and low propensity to induce serotonergic behaviors. These data suggest that selective biased agonists could constitute promising pharmacotherapeutics for mood disorders