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1.
J Med Chem ; 66(6): 3852-3865, 2023 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-36877935

RESUMO

Compounds that inhibit glutathione peroxidase 4 (GPX4) hold promise as cancer therapeutics in their ability to induce a form of nonapoptotic cell death called ferroptosis. Our research identified 24, a structural analog of the potent GPX4 inhibitor RSL3, that has much better plasma stability (t1/2 > 5 h in mouse plasma). The bioavailability of 24 provided efficacious plasma drug concentrations with IP dosing, thus enabling in vivo studies to assess tolerability and efficacy. An efficacy study in mouse using a GPX4-sensitive tumor model found that doses of 24 up to 50 mg/kg were tolerated for 20 days but had no effect on tumor growth, although partial target engagement was observed in tumor homogenate.


Assuntos
Ferroptose , Neoplasias , Camundongos , Animais , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Disponibilidade Biológica
2.
Elife ; 82019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30624206

RESUMO

The integrated stress response (ISR) attenuates the rate of protein synthesis while inducing expression of stress proteins in cells. Various insults activate kinases that phosphorylate the GTPase eIF2 leading to inhibition of its exchange factor eIF2B. Vanishing White Matter (VWM) is a neurological disease caused by eIF2B mutations that, like phosphorylated eIF2, reduce its activity. We show that introduction of a human VWM mutation into mice leads to persistent ISR induction in the central nervous system. ISR activation precedes myelin loss and development of motor deficits. Remarkably, long-term treatment with a small molecule eIF2B activator, 2BAct, prevents all measures of pathology and normalizes the transcriptome and proteome of VWM mice. 2BAct stimulates the remaining activity of mutant eIF2B complex in vivo, abrogating the maladaptive stress response. Thus, 2BAct-like molecules may provide a promising therapeutic approach for VWM and provide relief from chronic ISR induction in a variety of disease contexts.


Assuntos
Encefalopatias/etiologia , Fator de Iniciação 2B em Eucariotos/metabolismo , Estresse Psicológico/complicações , Substância Branca/patologia , Animais , Astrócitos/patologia , Encefalopatias/patologia , Encefalopatias/prevenção & controle , Doença Crônica , Fator de Iniciação 2B em Eucariotos/genética , Humanos , Masculino , Camundongos , Mutação , Proteínas do Tecido Nervoso/metabolismo , Oligodendroglia/patologia , Fosforilação , Biossíntese de Proteínas , Proteoma , Aumento de Peso
3.
J Neurophysiol ; 118(2): 904-916, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28468993

RESUMO

TRPV3 is a nonselective cation channel activated by temperatures above 33°C and is reported to be localized in keratinocytes and nervous tissue. To investigate a role for TRPV3 in pain modulation, we conducted a series of in vivo electrophysiological studies on spinal and brain nociceptive neurons. Structurally diverse TRPV3 receptor antagonists reduced responses of spinal wide dynamic range (WDR) neurons to low-intensity mechanical stimulation in neuropathic rats, but only CNS-penetrant antagonists decreased elevated spontaneous firing. Injections of an antagonist into the neuronal receptive field, into the L5 dorsal root ganglion, or intracerebroventricularly (ICV) attenuated the evoked firing, but only ICV injections reduced spontaneous activity. Intraspinal injections did not affect either. Spinal transection blocked the effect on spontaneous but not evoked firing after systemic delivery of a TRPV3 antagonist. Systemic administration of an antagonist to neuropathic rats also impacted the firing of On- and Off-cells in the rostral ventromedial medulla in a manner consistent with dampening nociceptive signaling. An assessment of nonevoked "pain," an EEG-measured pain-induced sleep disturbance induced by hind paw injections of CFA, was also improved with CNS-penetrant TRPV3 antagonists but not by an antagonist with poor CNS penetration. Antagonism of TRPV3 receptors modulates activity of key classes of neurons in the pain pathway in a manner consistent with limiting pathological nociceptive signaling and was mediated by receptors in the periphery and brain. Blockade of TRPV3 receptors is likely an effective means to alleviate mechanical allodynia and nonevoked pain. However, the latter will only be obtained by blocking supraspinal TRPV3 receptors.NEW & NOTEWORTHY Recent studies have linked TRPV3 to pain modulation, and much of this work has focused on its role in the skin-primary afferent interface. In this electrophysiological study, we demonstrate that receptor antagonists modulate evoked signals through peripheral mechanisms but blockade of supraspinal TRPV3 receptors contributes to dampening both evoked and nonevoked "pain" through descending modulation. Thus, the full therapeutic potential of TRPV3 antagonists may only be realized with the ability to access receptors in the brain.


Assuntos
Encéfalo/metabolismo , Gânglios Espinais/metabolismo , Dor Nociceptiva/metabolismo , Nociceptores/metabolismo , Medula Espinal/metabolismo , Canais de Cátion TRPV/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Masculino , Moduladores de Transporte de Membrana/química , Moduladores de Transporte de Membrana/farmacologia , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Dor Nociceptiva/tratamento farmacológico , Nociceptores/efeitos dos fármacos , Ratos Sprague-Dawley , Sono/efeitos dos fármacos , Sono/fisiologia , Medula Espinal/efeitos dos fármacos , Canais de Cátion TRPV/antagonistas & inibidores , Técnicas de Cultura de Tecidos
4.
J Org Chem ; 81(23): 12060-12064, 2016 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-27934457

RESUMO

An efficient asymmetric synthesis of dipyridyl TRPV3 antagonist 1 is reported. The four-step route involves two C-C bond-forming steps, a highly diastereoselective alkene hydration, and asymmetric ketone hydrosilylation in 97% ee.


Assuntos
Canais de Cátion TRPV/antagonistas & inibidores , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Piridinas/química , Espectrometria de Massas por Ionização por Electrospray , Estereoisomerismo
5.
J Med Chem ; 59(10): 4926-47, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27077528

RESUMO

Transient receptor potential vanilloid 3 (TRPV3) is a Ca(2+)- and Na(+)-permeable channel with a unique expression pattern. TRPV3 is found in both neuronal and non-neuronal tissues, including dorsal root ganglia, spinal cord, and keratinocytes. Recent studies suggest that TRPV3 may play a role in inflammation, pain sensation, and skin disorders. TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Herein, we provide the first detailed report on the development of potent and selective TRPV3 antagonists featuring a pyridinyl methanol moiety. Systematic optimization of pharmacological, physicochemical, and ADME properties of original lead 5a resulted in identification of a novel and selective TRPV3 antagonist 74a, which demonstrated a favorable preclinical profile in two different models of neuropathic pain as well as in a reserpine model of central pain.


Assuntos
Ciclobutanos/síntese química , Ciclobutanos/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Cálcio/metabolismo , Ciclobutanos/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Conformação Molecular , Piridinas/química , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismo
6.
Temperature (Austin) ; 2(2): 297-301, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-27227030

RESUMO

Transient receptor potential vanilloid 1 (TRPV1) is a multifunctional ion channel playing important roles in a numerous biological processes including the regulation of body temperature. Within distinct and tight chemical space of chromanyl ureas TRPV1 ligands were identified that exhibit distinctive pharmacology and a spectrum of thermoregulatory effects ranging from hypothermia to hyperthermia. The ability to manipulate these effects by subtle structural modifications of chromanyl ureas may serve as a productive approach in TRPV1 drug discovery programs addressing either side effect or desired target profiles of the compounds. Because chromanyl ureas in the TRPV1 context are generally antagonists, we verified observed partial agonist effects of a subset of compounds within that chemotype by comparing the in vitro profile of Compound 3 with known partial agonist 5'-I-RTX.

7.
Bioorg Med Chem Lett ; 22(7): 2604-8, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22370265

RESUMO

SAR studies on a series of thiophene amide derivatives provided CB(2) receptor agonists. The activity of the compounds was characterized by radioligand binding determination, multiple functional assays, ADME, and pharmacokinetic studies. A representative compound with selectivity for CB(2) over CB(1) effectively produced analgesia in behavioral models of neuropathic, inflammatory, and postsurgical pain. Control experiments using a CB(2) antagonist demonstrated the efficacy in the pain models resulted from CB(2) agonism.


Assuntos
Amidas/síntese química , Analgésicos/síntese química , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Receptor CB2 de Canabinoide/agonistas , Tiofenos/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Hiperalgesia/metabolismo , Neuralgia/metabolismo , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Tiofenos/farmacocinética , Tiofenos/farmacologia
8.
Br J Pharmacol ; 162(2): 428-40, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20880025

RESUMO

BACKGROUND AND PURPOSE: Cannabinoid CB2 receptor activation by selective agonists has been shown to produce analgesic effects in preclinical models of inflammatory and neuropathic pain. However, mechanisms underlying CB2-mediated analgesic effects remain largely unknown. The present study was conducted to elucidate the CB2 receptor expression in 'pain relevant' tissues and the potential sites of action of CB2 agonism in rats. EXPERIMENTAL APPROACH: Expression of cannabinoid receptor mRNA was evaluated by quantitative RT-PCR in dorsal root ganglia (DRGs), spinal cords, paws and several brain regions of sham, chronic inflammatory pain (CFA) and neuropathic pain (spinal nerve ligation, SNL) rats. The sites of CB2 mediated antinociception were evaluated in vivo following intra-DRG, intrathecal (i.t.) or intraplantar (i.paw) administration of potent CB2-selective agonists A-836339 and AM1241. KEY RESULTS: CB2 receptor gene expression was significantly up-regulated in DRGs (SNL and CFA), spinal cords (SNL) or paws (CFA) ipsilateral to injury under inflammatory and neuropathic pain conditions. Systemic A-836339 and AM1241 produced dose-dependent efficacy in both inflammatory and neuropathic pain models. Local administration of CB2 agonists also produced significant analgesic effects in SNL (intra-DRG and i.t.) and CFA (intra-DRG) pain models. In contrast to A-836339, i.paw administration of AM-1241 dose-relatedly reversed the CFA-induced thermal hyperalgesia, suggesting that different mechanisms may be contributing to its in vivo properties. CONCLUSIONS AND IMPLICATIONS: These results demonstrate that both DRG and spinal cord are important sites contributing to CB2 receptor-mediated analgesia and that the changes in CB2 receptor expression play a crucial role for the sites of action in regulating pain perception.


Assuntos
Analgésicos/farmacologia , Neuralgia/tratamento farmacológico , Dor/tratamento farmacológico , Receptor CB2 de Canabinoide/metabolismo , Analgesia , Analgésicos/uso terapêutico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Neuralgia/induzido quimicamente , Peptídeos Opioides/metabolismo , Dor/metabolismo , Percepção da Dor , RNA Mensageiro/análise , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Receptor CB2 de Canabinoide/agonistas , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Tiazóis/farmacologia , Tiazóis/uso terapêutico
9.
J Med Chem ; 53(1): 295-315, 2010 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-19921781

RESUMO

Several 3-acylindoles with high affinity for the CB(2) cannabinoid receptor and selectivity over the CB(1) receptor have been prepared. A variety of 3-acyl substituents were investigated, and the tetramethylcyclopropyl group was found to lead to high affinity CB(2) agonists (5, 16). Substitution at the N1-indole position was then examined. A series of aminoalkylindoles was prepared and several substituted aminoethyl derivatives were active (23-27, 5) at the CB(2) receptor. A study of N1 nonaromatic side chain variants provided potent agonists at the CB(2) receptor (16, 35-41, 44-47, 49-54, and 57-58). Several polar side chains (alcohols, oxazolidinone) were well-tolerated for CB(2) receptor activity (41, 50), while others (amide, acid) led to weaker or inactive compounds (55 and 56). N1 aromatic side chains also afforded several high affinity CB(2) receptor agonists (61, 63, 65, and 69) but were generally less potent in an in vitro CB(2) functional assay than were nonaromatic side chain analogues.


Assuntos
Indóis/farmacologia , Cetonas/farmacologia , Receptor CB2 de Canabinoide/agonistas , Desenho de Fármacos , Humanos , Indóis/síntese química , Indóis/química , Cetonas/síntese química , Cetonas/química , Ligantes , Estrutura Molecular , Receptor CB1 de Canabinoide/agonistas , Estereoisomerismo , Relação Estrutura-Atividade
10.
J Pharmacol Exp Ther ; 328(1): 141-51, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18931146

RESUMO

Studies demonstrating the antihyperalgesic and antiallodynic effects of cannabinoid CB(2) receptor activation have been largely derived from the use of receptor-selective ligands. Here, we report the identification of A-836339 [2,2,3,3-tetramethyl-cyclopropanecarboxylic acid [3-(2-methoxy-ethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]-amide], a potent and selective CB(2) agonist as characterized in in vitro pharmacological assays and in in vivo models of pain and central nervous system (CNS) behavior models. In radioligand binding assays, A-836339 displays high affinities at CB(2) receptors and selectivity over CB(1) receptors in both human and rat. Likewise, A-836339 exhibits high potencies at CB(2) and selectivity over CB(1) receptors in recombinant fluorescence imaging plate reader and cyclase functional assays. In addition A-836339 exhibits a profile devoid of significant affinity at other G-protein-coupled receptors and ion channels. A-836339 was characterized extensively in various animal pain models. In the complete Freund's adjuvant model of inflammatory pain, A-836339 exhibits a potent CB(2) receptor-mediated antihyperalgesic effect that is independent of CB(1) or mu-opioid receptors. A-836339 has also demonstrated efficacies in the chronic constrain injury (CCI) model of neuropathic pain, skin incision, and capsaicin-induced secondary mechanical hyperalgesia models. Furthermore, no tolerance was developed in the CCI model after subchronic treatment with A-836339 for 5 days. In assessing CNS effects, A-836339 exhibited a CB(1) receptor-mediated decrease of spontaneous locomotor activities at a higher dose, a finding consistent with the CNS activation pattern observed by pharmacological magnetic resonance imaging. These data demonstrate that A-836339 is a useful tool for use of studying CB(2) receptor pharmacology and for investigation of the role of CB(2) receptor modulation for treatment of pain in preclinical animal models.


Assuntos
Amidas/farmacologia , Ciclopropanos/farmacologia , Inflamação/fisiopatologia , Dor/fisiopatologia , Receptor CB1 de Canabinoide/fisiologia , Receptor CB2 de Canabinoide/fisiologia , Animais , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Procedimentos Cirúrgicos Dermatológicos , Membro Posterior , Humanos , Hiperalgesia/fisiopatologia , Rim/embriologia , Imageamento por Ressonância Magnética/métodos , Masculino , Dor Pós-Operatória/fisiopatologia , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Ratos , Ratos Sprague-Dawley , Receptor CB2 de Canabinoide/agonistas
11.
J Med Chem ; 51(6): 1904-12, 2008 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-18311894

RESUMO

A series of potent indol-3-yl-tetramethylcyclopropyl ketones have been prepared as CB 2 cannabinoid receptor ligands. Two unsubstituted indoles ( 5, 32) were the starting points for an investigation of the effect of indole ring substitutions on CB 2 and CB 1 binding affinities and activity in a CB 2 in vitro functional assay. Indole ring substitutions had varying effects on CB 2 and CB 1 binding, but were generally detrimental to agonist activity. Substitution on the indole ring did lead to improved CB 2/CB 1 binding selectivity in some cases (i.e., 7- 9, 15- 20). All indoles with the morpholino-ethyl side chain ( 32- 43) exhibited weaker binding affinity and less agonist activity relative to that of their tetrahydropyranyl-methyl analogs ( 5- 31). Several agonists were active in the complete Freund's adjuvant model of chronic inflammatory thermal hyperalgesia ( 32, 15).


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Indóis/farmacologia , Cetonas/farmacologia , Receptor CB2 de Canabinoide/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Ligação Competitiva , Linhagem Celular , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Indóis/síntese química , Indóis/química , Cetonas/síntese química , Cetonas/química , Ligantes , Conformação Molecular , Ratos , Receptor CB1 de Canabinoide/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade
12.
J Med Chem ; 50(15): 3627-44, 2007 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-17585748

RESUMO

A series of exceptionally potent agonists at neuronal nicotinic acetylcholine receptors (nAChRs) has been investigated. Several N-(3-pyridinyl) derivatives of bridged bicyclic diamines exhibit double-digit-picomolar binding affinities for the alpha 4 beta 2 subtype, placing them with epibatidine among the most potent nAChR ligands described to date. Structure-activity studies have revealed that substitutions, particularly hydrophilic groups in the pyridine 5-position, differentially modulate the agonist activity at ganglionic vs central nAChR subtypes, so that improved subtype selectivity can be demonstrated in vitro. Analgesic efficacy has been achieved across a broad range of pain states, including rodent models of acute thermal nociception, persistent pain, and neuropathic allodynia. Unfortunately, the hydrophilic pyridine substituents that were shown to enhance agonist selectivity for central nAChRs in vitro tend to limit CNS penetration in vivo, so that analgesic efficacy with an improved therapeutic window was not realized with those compounds.


Assuntos
Analgésicos/síntese química , Diaminas/síntese química , Compostos Heterocíclicos de Anel em Ponte/síntese química , Agonistas Nicotínicos/síntese química , Piridinas/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Ligação Competitiva , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Diaminas/química , Diaminas/farmacologia , Dopamina/metabolismo , Compostos Heterocíclicos de Anel em Ponte/química , Compostos Heterocíclicos de Anel em Ponte/farmacologia , Técnicas In Vitro , Ligantes , Modelos Moleculares , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacologia , Dor/tratamento farmacológico , Dor/etiologia , Medição da Dor , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Piridinas/química , Piridinas/farmacologia , Ratos , Receptores Nicotínicos/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
13.
Epilepsia ; 46(9): 1349-61, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16146429

RESUMO

PURPOSE: The objective of this study was to characterize the antiseizure and safety profiles of ABT-769 [(R)-N-(2 amino-2-oxoethyl)spiro[2,5]octane-1-carboxamide]. METHODS: ABT-769 was tested for protection against maximal electroshock and pentylenetetrazol-induced seizures in the mouse and for suppression of electrically kindled amygdala seizures and spontaneous absence-like seizures in the rat. The central nervous system safety profile was evaluated by using tests of motor coordination and inhibitory avoidance. The potential for liver toxicity was assessed in vitro by using a mitochondrial fatty acid beta-oxidation assay. Teratogenic potential was assessed in the mouse. RESULTS: ABT-769 blocked maximal electroshock, subcutaneous pentylenetetrazol and intravenous pentylenetetrazol-induced seizures with median effective dose (ED50) values of 0.25, 0.38, and 0.11 mmol/kg, p.o., respectively. No tolerance was evident in the intravenous pentylenetetrazol test after twice-daily dosing of ABT-769 (0.3 mmol/kg, p.o.) for 4 days. ABT-769 blocked absence-like spike-wave discharge (ED50, 0.15 mmol/kg, p.o.) and shortened the cortical and amygdala afterdischarge duration of kindled seizures (1 and 3 mmol/kg, p.o.). The protective indices (ED50 rotorod impairment/ED50 seizure protection) were 4.8, 3.2, and 10.9 in the maximal electroshock, subcutaneous pentylenetetrazol and intravenous pentylenetetrazol seizure tests, respectively. ABT-769 did not affect inhibitory avoidance performance (0.1-1 mmol/kg, p.o.). ABT-769 did not affect mitochondrial fatty acid beta-oxidation or induce neural tube defects. CONCLUSIONS: ABT-769 is an efficacious antiseizure agent in animal models of convulsive and nonconvulsive epilepsy and has a favorable safety profile. ABT-769 has a broad-spectrum profile like that of valproic acid. Its profile is clearly different from those of carbamazepine, phenytoin, lamotrigine, topiramate, vigabatrin, and tiagabine.


Assuntos
Anticonvulsivantes/farmacologia , Anticonvulsivantes/toxicidade , Comportamento Animal/efeitos dos fármacos , Epilepsia/prevenção & controle , Ácido Valproico/análogos & derivados , Ácido Valproico/farmacologia , Anormalidades Induzidas por Medicamentos/epidemiologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiopatologia , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Eletrochoque , Epilepsia/induzido quimicamente , Epilepsia/metabolismo , Epilepsia Tipo Ausência/induzido quimicamente , Epilepsia Tipo Ausência/metabolismo , Epilepsia Tipo Ausência/prevenção & controle , Humanos , Injeções Intravenosas , Injeções Subcutâneas , Excitação Neurológica/efeitos dos fármacos , Excitação Neurológica/metabolismo , Excitação Neurológica/fisiologia , Masculino , Camundongos , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Pentilenotetrazol/administração & dosagem , Ratos , Ratos Wistar , Especificidade da Espécie , Compostos de Espiro/farmacologia , Compostos de Espiro/toxicidade , Ácido Valproico/toxicidade
14.
Curr Top Med Chem ; 4(3): 299-334, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-14754449

RESUMO

In the last decade, nicotinic acetylcholine receptors (nAChRs) have emerged as important targets for drug discovery. The therapeutic potential of nicotinic agonists depends substantially on the ability to selectively activate certain receptor subtypes that mediate beneficial effects. The design of such compounds has proceeded in spite of a general shortage of data pertaining to subtype selectivity. Medicinal chemistry efforts have been guided principally by binding affinities to the alpha4beta2 and/or alpha7 subtypes, even though these are not predictive of agonist activity at either subtype. Nevertheless, a diverse family of nAChR ligands has been developed, and several analogs with promising therapeutic potential have now advanced to human clinical trials. This paper provides an overview of the structure-affinity relationships that continue to drive development of new nAChR ligands.


Assuntos
Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais , Desenho de Fármacos , Humanos , Ligantes , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/metabolismo , Receptores Nicotínicos/metabolismo
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