These considerations highlight the ongoing medical need for novel and well-tolerated antidepressant drugs. Nevertheless, ketamine presents several notable limitations that prevent its widespread use as an antidepressant, including the induction of dissociative states which may be difficult to separate from the antidepressant effects, (13,14) cardiovascular and urinary tract side effects, (15−17) and neurotoxicity and neurocognitive dysfunction. (12) These results strongly suggest that mechanisms that elicit robust activation of cortical ERK phosphorylation could constitute an effective and novel strategy to discover improved antidepressant drugs which, like ketamine, could (i) show efficacy in profoundly depressed and treatment-resistant patients, (ii) be effective following short durations of treatment (or even acutely, like ketamine), and (iii) target new neurobiological mechanisms distinct from classical monoamine reuptake inhibitors. Indeed, ketamine elicits robust phosphorylation of ERK in this brain region, (9−11) and correspondingly, inhibition of ERK phosphorylation using inhibitors of mitogen-activated proteins kinase (MEK) blocked the antidepressant-like effects of ketamine in rat models, an observation that was also seen with another NMDA receptor antagonist, Ro 25-6981. The latter mechanism has attracted considerable attention as a substrate for ketamine’s antidepressant activity. (6−8) At a molecular level, ketamine was found to mediate its antidepressant effects in rats via several mechanisms including AMPA and mTOR activation and, of particular interest in the present context, extracellular regulated kinase (ERK) phosphorylation in prefrontal cortex (PFC). Accordingly, the S-enantiomer of ketamine is currently being evaluated by the FDA as a rapid-acting antidepressant for treatment-resistant depression. Indeed, the discovery that ketamine, a general anesthetic drug acting primarily as a noncompetitive N-methyl- d-aspartate (NMDA) receptor antagonist, can reverse depressive symptoms in profoundly depressed and treatment-resistant patients has given new hope that depressive states can be treated efficaciously and rapidly. (4,5) Nevertheless, recent findings suggest that the development of rapidly acting and highly clinically efficacious novel antidepressants is a realistic prospect. (2,3) Furthermore, current antidepressants usually require several weeks of administration before clinical efficacy is observed-this protracted delay in therapeutic onset is a source of distress to families, of increased medical burden, and of potential suicide risk for patients. (1) The clinical efficacy of this strategy is less than optimal, as indicated by the substantial proportion of patients that fail to respond to treatment or that show only partial treatment response.
With few exceptions, current antidepressants target inhibition of monoamine neurotransmitter reuptake into brain neurons. These data suggest that the present 5-HT 1A receptor-biased agonists could constitute promising antidepressant drug candidates.ĭespite the clinical availability of a large number of antidepressant drugs, the treatment of depressive disorders still remains an area of unmet medical need. 17 also robustly stimulated ERK1/2 phosphorylation in rat cortex and showed highly potent (MED = 0.16 mg/kg) and efficacious antidepressant-like activity, totally eliminating immobility in the rat Porsolt test. Preliminary in vivo studies confirmed its promising pharmacokinetic profile. The lead structure, (3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone ( 17, NLX-204), displayed high selectivity in the SafetyScreen44 panel (including hERG channel), high solubility, metabolic stability, and Caco-2 penetration and did not block CYP3A4, CYP2D6 isoenzymes, or P-glycoprotein.
#SOUND NORMALIZER V7.99.7 SERIES#
The novel series showed high 5-HT 1A receptor affinity, >1000-fold selectivity versus noradrenergic α 1, dopamine D 2, serotonin 5-HT 2A, histamine H 1, and muscarinic M 1 receptors, and favorable druglike properties (CNS-MPO, Fsp 3, LELP). The compounds were tested in signal transduction assays (ERK1/2 phosphorylation, cAMP inhibition, Ca 2+ mobilization, and β-arrestin recruitment) which identified ERK1/2 phosphorylation-preferring aryloxyethyl derivatives. Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives were designed as “biased agonists” of serotonin 5-HT 1A receptors.
0 kommentar(er)
