Partial Dopamine D2/Serotonin 5-HT1A Receptor Agonists as New Therapeutic Agents~!2009-12-17~!2010-04-07~!2010-07-20~!

Abstract

Abstract:The therapeutic efficacy of current antipsychotic or antidepressant agents still present important drawbacks such as delayed onset of action and a high percentage of non-responders. Despite significant advancements in the development of new drugs with more acceptable side-effect profiles, patients with schizophrenia or major depression experience substantial disability and burden of disease. The present review discusses the usefulness of partial dopamine D 2 /serotonin 5-HT 1A receptors agonists in the treatment of schizophrenia, major depression and bipolar disorder as well as in Parkinson's disease. Partial agonists can behave as modulators since their intrinsic activity or efficacy of a partial agonist depends on the target receptor population and the local concentrations of the natural neurotransmitter. Thus, these drugs may restore adequate neurotransmission while inducing less side effects. In schizophrenia, partial DA D 2 /5-HT 1A receptor agonists (like aripiprazole or bifeprunox), by stabilizing DA system via a preferential reduction of phasic DA release, reduce side effects i.e. extrapyramidal symptoms and improve cognition by acting on 5-HT 1A receptors. Aripiprazole appears also as a promising agent for the treatment of depression since it potentiates the effect of SSRIs in resistant treatment depression. Concerning bipolar disorders aripiprazole may have only a benefit effect in the treatment of manic episodes. Conversely, treatment of Parkinson's disease with partial DA D 2 /5-HT 1A receptor agonists remains still experimental. However several studies suggest that these drugs decrease usually observed side effects (dyskinesia, psychoticlike symptoms) in Parkinson's disease treatment. Hence, these relatively recent researches provide an exciting future in the discovery of novel stabilizators agents for the management of the latter diseases.

Synthesis of Novel Pyrido[1,2-c]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT1A Receptor Ligands

“…It has been confirmed that disturbed dopaminergic neurotransmission in the mesolimbic and nigrostriatal regions also contributes significantly to the development of depression [ 32 ]. Consequently, intensive research is under way on a new class of potential drugs which exert their effects through interaction with D 2 /5-HT 1A [ 33 ]; where the ligand would be a partial agonist of the 5-HT 1A receptor and would induce postsynaptic serotonergic neurotransmission, which would increase dopamine levels in the mPFC (medial prefrontal cortex) [ 34 ]. The role of 5-HT 2A receptors in the treatment of schizophrenia has also been well documented in numerous publications.…”

Role of 5-HT3 Receptors in the Antidepressant Response

“…For example, stress, in animal models of depression, activates VTA DA neurons and their limbic efferent targets [ 115 ]. Moreover, the DA system is now one of the targets of depression treatment, for example drugs initially used in schizophrenia like aripiprazole or quetiapine are now used in depressed patients [ 8 ].…”

“…Preclinical studies have suggested that targeting specific 5-HT receptors with selective agonist or antagonist drugs may enhance the antidepressant response and reduced its delay compared to currently used antidepressants. Both the 5-HT 1A receptor antagonist pindolol and 5-HT 1A receptor agonists, e.g., buspirone, have been largely investigated both in clinical and in preclinical studies in combination with antidepressants with some significant effects [ 7 , 8 ]. Moreover, the beneficial effect of atypical antipsychotics, such as quietapine, in combination with antidepressants in depression may be partly due to their 5-HT 2A receptor targeting [ 9 , 10 ].…”

A method for rapid screening of interactions of pharmacologically active compounds with albumin

“…The compounds were obtained in a search for a new generation of antipsychotics following the principles of the multitarget strategy. The derivatives were designed for 5-HT 2A and D 2 receptors (the basic profile of pharmaceutical activity of atypical antipsychotics) and, additionally, for 5-HT 1A receptors [19][20][21][22][23][24][25]. With the aim of enhancing cognitive factors and memory, which might be improved by potential antipsychotics [26], the activity of the compounds was expanded to their affinity to 5-HT 1A receptors.…”

“…The role played by the 5-HT 1A receptor in the pathomechanism of schizophrenia was related to its regulatory influence on the functions of the prefrontal cortex (PFC), including emotional control, cognitive behavior and working memory [26][27][28][29][30][31]. The goal of the research was to obtain a new generation of antipsychotics which would display a multireceptor mechanism of action, be devoid of many undesired effects such as extrapyramidal symptoms (EPS), tardive dyskinesia or weight gain in patients and many other effects caused by drugs currently used in the pharmacotherapy of schizophrenia [21,22,32].…”