Schizophrenia is a complex disorder affecting approximately 1% of the population. Typical antipsychotic agents such as chlorpromazine and haloperidol block the D2 subtype of dopamine receptors in a direct relation to their clinical potency. However, although blockade of D2 receptors improves the positive symptoms of the disease, it also accounts for side effects which strongly limit patient compliance, in particular extrapyramidal effects and hyperprolactinemia. During the past few years, a second generation of antipsychotic agents has emerged (e.g.,clozapine, risperidone, olanzapine, and ziprasidone); they are categorized as atypical in contrast to conventional D2 blockers and exhibit a dual dopaminergic and serotonergic mechanism of action: a relatively weak dopamine D2 receptor antagonism in vitro and in vivo, but potentially important activities at other dopaminergic (D1, D4) receptors, at serotonergic (5-HT1A, 5HT2A, 5HT3, 5HT2C), adrenergic (a1, a2), histaminergic (H1), and muscarinic receptors. They are claimed to be active against both positive and negative symptoms of schizophrenia, even though they do exhibit a variety of other side effects as weight gain, postural hypotension, sedation, dry mouth. For these reasons the search for more effective and less toxic agents still continues [1,2]. In this context we have developed a series of (1,2-diphenyl-imidazolyl)piperazine derivatives (1) that are endowed with substantial affinities for both dopamine D2 receptors as well as 5-HT1A and 5-HT2A serotonin receptors, compound 1a (R = o-OCH3) of which is representative . We have extended our study on other series of compounds derived from 1 both modifying the 1,2-diphenyl motif attached to the imidazole core, and the phenyl-piperazine moiety. All novel compounds were submitted by Lundbeck to radioligand binding assay on dopamine, serotonin, adrenergic, histaminergic receptor subtypes. The chemistry and the in vitro screening will be discussed in the poster.
|Titolo:||Synthesis and sar study of 2-substituted imidazo[2,1-b] [1,3]benzothiazoles and related compounds endowed with affinity for dopamine d2 receptors as potential antipsychotics|
MURA, STEFANIA (Penultimo)
|Data di pubblicazione:||2008|
|Citazione:||Synthesis and sar study of 2-substituted imidazo[2,1-b] [1,3]benzothiazoles and related compounds endowed with affinity for dopamine d2 receptors as potential antipsychotics / B. Asproni, J. Kehler, S. Simula, S. Mura, G. Porcu. ((Intervento presentato al convegno Sardinia Chem : Giornata di studio dedicata alla chimica organica delle molecole biologicamente attive tenutosi a Sassari nel 2008.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|