RESUMO
All clinically-used antipsychotics display similar affinity for both D2 (D2R) and D3 (D3R) receptors, and they likewise act as 5-HT2A receptor antagonists. They provide therapeutic benefit for positive symptoms, but no marked or consistent improvement in neurocognitive, social cognitive or negative symptoms. Since blockade of D3 and 5-HT6 (5-HT6R) receptors enhances neurocognition and social cognition, and potentially improves negative symptoms, a promising approach for improved treatment for schizophrenia would be to develop drugs that preferentially act at D3R versus D2R and likewise recognize 5-HT6R. Starting from the high affinity 5-HT6R ligands I and II, we identified compounds 11a and 14b that behave as 5-HT6R ligands with significant selectivity for D3R over D2R.
Assuntos
Antipsicóticos/química , Antipsicóticos/farmacologia , Desenho de Fármacos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Humanos , Indóis/química , Indóis/farmacologia , Simulação de Acoplamento Molecular , Compostos Policíclicos/química , Compostos Policíclicos/farmacologia , Esquizofrenia/tratamento farmacológico , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologiaRESUMO
A general methodology for the stereoselective synthesis of 2-(2-hydroxyalkyl)piperidine alkaloids by ring-rearrangement metathesis of nitroso Diels-Alder cycloadducts is reported. The approach is illustrated by the formal synthesis of porantheridine and the total synthesis of andrachcinidine through a diastereodivergent allylation of an N-alkoxy bicyclic lactam. The asymmetric synthesis of the latter alkaloid provides new insights into the configurational stability of cycloadducts between chloronitroso reagents and cyclopentadiene.
Assuntos
Alcaloides/síntese química , Lactamas/química , Piperidinas/síntese química , Alquilação , Estrutura Molecular , EstereoisomerismoRESUMO
The application of a sequence involving a nitroso Diels-Alder cycloaddition and a ring-rearrangement metathesis to the total synthesis of (+/-)-8-epihalosaline and the formal synthesis of (+/-)-porantheridine is described. The formation of the 2,6-trans-disubstituted piperidine backbone of porantheridine has been accomplished by addition of a Grignard reagent onto an N-benzylpiperidone followed by a highly diastereoselective reduction of the imminium intermediate in one pot.
Assuntos
Alcaloides/síntese química , Compostos Nitrosos/química , Piperidinas/síntese química , Alcaloides/química , Ciclização , Estrutura Molecular , Piperidinas/química , EstereoisomerismoRESUMO
Pleiotropic intervention may be a requirement for effective limitation of the progression of multifactorial diseases such as Alzheimer's Disease. One approach to such intervention is to design a single chemical entity capable of acting on two or more targets of interest, which are accordingly known as Multi-Target Directed Ligands (MTDLs). We recently described donecopride, the first MTDL able to simultaneously inhibit acetylcholinesterase and act as an agonist of the 5-HT4 receptor, which displays promising activities in vivo. Pharmacomodulation of donecopride allowed us to develop a novel series of indole derivatives possessing interesting in vitro activities toward AChE and the σ1 receptor. The crystal structures of complexes of the most promising compounds with Torpedo californica AChE were solved in order to further understand their mode of inhibition.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/síntese química , Indóis/farmacologia , Agonistas do Receptor 5-HT4 de Serotonina/síntese química , Acetilcolinesterase/efeitos dos fármacos , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Inibidores da Colinesterase/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Indóis/síntese química , Ligantes , Piperidinas/química , Piperidinas/farmacologia , Receptores 5-HT4 de Serotonina/efeitos dos fármacos , Agonistas do Receptor 5-HT4 de Serotonina/farmacologia , TorpedoRESUMO
Alzheimer's disease (AD) is the most common form of dementia affecting millions of patients worldwide which can only be treated with symptomatic drugs. Among the numbers of biological targets which are today explored in order to prevent or limit the progression of AD, the modulation of 5-HT6R and 5-HT4R appeared to be promising. This modulation has been proved to enhance the cognition in AD through modulation of the neurotransmitter system but could also be beneficial in order to limit the amyloid pathology. This review will describe recent advances in the understanding of this modulation as well as the medicinal chemistry of 5-HT6R or 5-HT4R ligands from synthesis to ongoing clinical trials.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Química Farmacêutica , Humanos , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/químicaRESUMO
Given its predominant expression in the central nervous system (CNS), 5-hydroxytryptamine (5-HT: serotonin) subtype 6 receptor (5-HT6R) has been considered as a valuable target for the development of CNS drugs with limited side effects. After 2 decades of intense research, numerous selective ligands have been developed to target this receptor; this holds potential interest for the treatment of neuropathological disorders. In fact, some agents (mainly antagonists) are currently undergoing clinical trial. More recently, a series of potent and selective agonists have been developed, and preclinical studies have been conducted that suggest the therapeutic interest of 5-HT6R agonists. This review details the medicinal chemistry of these agonists, highlights their activities, and discusses their potential for treating cognitive issues associated with Alzheimer's disease (AD), depression, or obesity. Surprisingly, some studies have shown that both 5-HT6R agonists and antagonists exert similar procognitive activities. This article summarizes the hypotheses that could explain this paradox.
Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/uso terapêutico , Animais , Humanos , Modelos Moleculares , Conformação Molecular , Nootrópicos/farmacologia , Antagonistas da Serotonina/farmacologiaRESUMO
A copper(I)-catalyzed reaction of a variety of 4-aryl-pent-4-enoates with nosyliminoiodane generated in situ provides the corresponding 5-aryl-5-nosylamidomethylbutyrolactones. The reaction presumably proceeds via an aziridine intermediate, which could be isolated in one case.