RESUMO
We have demonstrated the utility of a 3D shape and pharmacophore similarity scoring component in molecular design with a deep generative model trained with reinforcement learning. Using Dopamine receptor type 2 (DRD2) as an example and its antagonist haloperidol 1 as a starting point in a ligand based design context, we have shown in a retrospective study that a 3D similarity enabled generative model can discover new leads in the absence of any other information. It can be efficiently used for scaffold hopping and generation of novel series. 3D similarity based models were compared against 2D QSAR based, indicating a significant degree of orthogonality of the generated outputs and with the former having a more diverse output. In addition, when the two scoring components are combined together for training of the generative model, it results in more efficient exploration of desirable chemical space compared to the individual components.
Assuntos
Desenho de Fármacos , Haloperidol/farmacologia , Receptores de Dopamina D2/metabolismo , Haloperidol/síntese química , Haloperidol/química , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Relação Estrutura-AtividadeRESUMO
Two types of haloperidol prodrugs in which a chemical modification was carried out on the hydroxyl group or carbonyl group were synthesized, and their metabolic activation abilities were evaluated in a human liver microsome (HLM) solution, a human small intestine microsome (HIM) solution and solutions of human recombinant carboxylesterases (hCESs). The metabolic activation rates of alcohol ester prodrugs in HLM solution were similar to those in hCES2 solution, and haloperidol pentanoate and haloperidol hexanoate showed high metabolic activation rates in the synthesized alcohol ester prodrugs. In addition, haloperidol acetate and haloperidol 2-methylbutanoate were hydrolyzed as slowly as haloperidol decanoate. The results suggested that haloperidol prodrugs with a small chain or a branched chain are useful as prodrugs for sustained release. The metabolic activation rate of the enol ester prodrug in HLM solution was similar to that in hCES1 solution, and the enol ester prodrug was found to behave differently from alcohol ester prodrugs, which were metabolically activated by hCES2.
Assuntos
Carboxilesterase/metabolismo , Haloperidol/análogos & derivados , Haloperidol/síntese química , Microssomos/enzimologia , Pró-Fármacos/síntese química , Estabilidade de Medicamentos , Ésteres , Haloperidol/metabolismo , Humanos , Técnicas In Vitro , Inativação Metabólica , Intestino Delgado/enzimologia , Microssomos Hepáticos/enzimologia , Estrutura Molecular , Pró-Fármacos/metabolismoRESUMO
A mechanism that enables direct aldehyde C-H functionalization has been achieved via the synergistic merger of photoredox, nickel, and hydrogen atom transfer catalysis. This mild, operationally simple protocol transforms a wide variety of commercially available aldehydes, along with aryl or alkyl bromides, into the corresponding ketones in excellent yield. This C-H abstraction coupling technology has been successfully applied to the expedient synthesis of the medicinal agent haloperidol.
Assuntos
Aldeídos/química , Antieméticos/síntese química , Haloperidol/síntese química , Hidrocarbonetos Aromáticos/química , Hidrogênio/química , Níquel/química , Aldeídos/síntese química , Alquilação , Antieméticos/química , Brometos/síntese química , Brometos/química , Catálise , Haloperidol/química , Hidrocarbonetos Aromáticos/síntese química , Oxirredução , Processos FotoquímicosRESUMO
As the number of hospitalized and immunocompromised patients continues to rise, invasive fungal infections, such as invasive candidiasis and aspergillosis, threaten the life of millions of patients every year. The azole antifungals are currently the most prescribed drugs clinically that display broad-spectrum antifungal activity and excellent oral bioavailability. Yet, the azole antifungals have their own limitations and are unable to meet the challenges associated with increasing fungal infections and the accompanied development of resistance against azoles. Exploring combination therapy that involves the current azoles and another drug has been shown to be a promising strategy. Haloperidol and its derivative, bromperidol, were originally discovered as antipsychotics. Herein, we synthesize and report a series of bromperidol derivatives and their synergistic antifungal interactions in combination with a variety of current azole antifungals against a wide panel of fungal pathogens. We further select two representative combinations and confirm the antifungal synergy by performing time-kill assays. Furthermore, we evaluate the ability of selected combinations to destroy fungal biofilm. Finally, we perform mammalian cytotoxicity assays with the representative combinations against three mammalian cell lines.
Assuntos
Antifúngicos/farmacologia , Antipsicóticos/farmacologia , Azóis/farmacologia , Fungos/efeitos dos fármacos , Haloperidol/análogos & derivados , Micoses/tratamento farmacológico , Animais , Antifúngicos/síntese química , Antifúngicos/química , Antipsicóticos/síntese química , Antipsicóticos/química , Azóis/síntese química , Azóis/química , Biofilmes/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Haloperidol/síntese química , Haloperidol/química , Haloperidol/farmacologia , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
(±)-MRJF22 [(±)-2], a novel prodrug of haloperidol metabolite II (sigma-1 receptor antagonist/sigma-2 receptor agonist ligand) obtained by conjugation to valproic acid (histone deacetylase inhibitor) via an ester bond, exhibits antiangiogenic activity, being able to reduce human retinal endothelial cell (HREC) viability in a comparable manner to bevacizumab. Moreover, (±)-2 was able to significantly reduce viable cells count, endothelial cell migration, and tube formation in vascular endothelial growth factor A (VEGF-A) stimulated HREC cultures.
Assuntos
Inibidores da Angiogênese/farmacologia , Células Endoteliais/efeitos dos fármacos , Haloperidol/farmacologia , Microvasos/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Retina/citologia , Ácido Valproico/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Endoteliais/citologia , Haloperidol/síntese química , Haloperidol/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Ácido Valproico/síntese química , Ácido Valproico/químicaRESUMO
A novel method of greatly increasing solubility and dissolution rate of a model basic drug, haloperidol, by interacting it with water-soluble weak organic acids in aqueous media was previously reported in the literature. Amorphous solid dispersion (SD) was formed when solutions containing haloperidol and various acids were dried. However, the SDs were semisolid, viscous and sticky, especially when the drug load was high, and could not be processed into tablets. The drug release from SD was also incomplete since the viscous material did not readily mix with aqueous media. In the present study, a mesoporous metalosilicate, Neusilin(®) US2, was incorporated in SDs prepared by using malic, tartaric and citric acids. The silicate constituted 40% w/w of the total solid mass. The addition of silicate converted SDs into powders, which were then characterized for flow properties, bulk and tap density, and tabletability. Their physical properties were found to be acceptable for the development of tablets. DSC and powder XRD showed that haloperidol and acids converted completely to amorphous forms, and they did not show any sign of crystallization during accelerated stability study at 40°C/75% RH and 25°C/60% RH for 9 months. Complete drug release under gastrointestinal pH conditions could be obtained from tablets prepared.
Assuntos
Compostos de Alumínio/química , Química Farmacêutica/métodos , Haloperidol/síntese química , Compostos de Magnésio/química , Excipientes Farmacêuticos/química , Silicatos/química , Concentração de Íons de Hidrogênio , Pós , Solubilidade , Comprimidos , Difração de Raios XRESUMO
In a previous work we reported the antiproliferative effects of (±)-MRJF4, a novel haloperidol metabolite II (HP-mII) (a sigma-1 antagonist and sigma-2 agonist) prodrug, obtained through conjugation to 4-phenylbutyric acid (PhBA) [a histone deacetylase inhibitor (HDACi)] via an ester bond. As a continuation of this work, here we report the asymmetric synthesis of compounds (R)-(+)-MRJF4 and (S)-(-)-MRJF4 and the evaluation of their biological activity on rat C6 glioma cells, derived from glioblastoma multiforme (GBM), which is the most common and deadliest central nervous system (CNS) invasive malignancy. Favourable physicochemical properties, high permeability in the parallel artificial membrane permeability assay (PAMPA), good enzymatic and chemical stability, in vivo anticancer activity, associated with the capacity to reduce cell viability and to increase cell death by apoptosis, render compound (R)-(+)-MRJF4 a promising candidate for the development of a useful therapeutic for gliomas therapy.
Assuntos
Antineoplásicos/farmacologia , Glioma/tratamento farmacológico , Haloperidol/farmacologia , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioma/patologia , Haloperidol/síntese química , Haloperidol/metabolismo , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo , Ratos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Homodimers of dopamine D2-like receptors are suggested to be of particular importance in the pathophysiology of schizophrenia and, thus, serve as promising targets for the discovery of atypical antipsychotics. This study describes the development of a series of novel bivalent molecules with a pharmacophore derived from the dopamine receptor antagonist haloperidol. These dimers were investigated in comparison to their monomeric analogues for their D2long, D2short, D3, and D4 receptor binding and the ability to bridge two neighboring receptor protomers. Radioligand binding studies provided diagnostic insights when Hill slopes close to two for the bivalent ligand 13 incorporating 22 spacer atoms and a comparative analysis with monovalent control ligands indicated a bivalent binding mode with a simultaneous occupancy of two neighboring binding sites.
Assuntos
Haloperidol/farmacologia , Receptores de Dopamina D2/metabolismo , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Haloperidol/síntese química , Haloperidol/química , Humanos , Ligantes , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
D2-like receptors are members of dopamine receptors, including dopamine D2 receptor (D2R), dopamine D3 receptor (D3R), and dopamine D4 receptor (D4R), which modulate behavior, cognition, and emotion. D2-like receptors are critical targets for drug development. Particularly, D3R has been identified as a therapeutic target for antipsychotic and anti-parkinsonian drugs. Recently, the crystal structure of D3R was reported. Here we summarize the available active compounds for D3R and the structure-activity relationships (SAR) studies of them. This provides lead templates for further chemical modification. We describe the structure features of the recent crystal structure of D3R and its difference from other G protein-coupled receptors (GPCRs). We provide the recognition mechanism of the inhibitors of D3R (molecular docking results and molecular dynamics results), which illustrates the interaction between the inhibitors and critical residues of D3R. Finally, we summarize the outlook of drug development for D3R. Our study provides useful information for developing high selective, high potent antagonists and agonists of D3R.
Assuntos
Desenho de Fármacos , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Técnicas de Química Combinatória , Haloperidol/análogos & derivados , Haloperidol/síntese química , Haloperidol/farmacologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Camundongos , Modelos Moleculares , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacologia , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Espiperona/análogos & derivados , Espiperona/síntese química , Espiperona/farmacologia , Relação Estrutura-Atividade , Sulpirida/análogos & derivados , Sulpirida/síntese química , Sulpirida/farmacologia , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologiaRESUMO
Structure-activity relationship studies on 4-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-1-(4-fluorophenyl)butan-1-one (SYA 013), a homopiperazine analog of haloperidol has resulted in an understanding of the effect of structural modifications on binding affinity at dopamine and serotonin receptor subtypes. Further exploration, using bioisosteric replacement strategies has led to the identification of several new agents including compounds 7, 8, 11 and 12 which satisfy the initial criteria for further exploration as new antipsychotic agents. In addition, compound 18, a D(3) selective tropanol, has been identified as having the potential for further optimization into a useful drug which may combat neuropsychiatric diseases.
Assuntos
Azepinas/química , Azepinas/farmacologia , Haloperidol/análogos & derivados , Antipsicóticos/síntese química , Antipsicóticos/química , Antipsicóticos/farmacologia , Azepinas/síntese química , Haloperidol/síntese química , Haloperidol/química , Haloperidol/farmacologia , Relação Estrutura-AtividadeRESUMO
Several haloperidol derivatives with a piperidine scaffold that was decorated at the nitrogen atom with different alkyl, benzyl, or substituted benzyl moieties were synthesized at our laboratory to establish a library of compounds with vasodilator activity. Compounds were screened for vasodilatory activity on isolated thoracic aorta rings from rats, and their quantitative structure-activity relationships (QSAR) were examined. Based on the result of QSAR, N-4-tert-butyl benzyl haloperidol chloride (16c) was synthesized and showed the most potent vasodilatory activity of all designed compounds. 16c dose-dependently inhibited the contraction caused by the influx of extracellular Ca(2+) in isolated thoracic aorta rings from rats. It concentration-dependently attenuated the calcium channel current and extracellular Ca(2+) influx, without affecting the intracellular Ca(2+) mobilization, in vascular smooth muscle cells from rats. 16c, possessing the N-4-tert-butyl benzyl piperidine structure, as a novel calcium antagonist, may be effective as a calcium channel blocker in cardiovascular disease.
Assuntos
Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/farmacologia , Desenho de Fármacos , Haloperidol/síntese química , Haloperidol/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Aorta Torácica/citologia , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio Tipo L/metabolismo , Relação Dose-Resposta a Droga , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Haloperidol/análogos & derivados , Haloperidol/química , Técnicas In Vitro , Espaço Intracelular/efeitos dos fármacos , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Cloreto de Potássio/farmacologia , Relação Quantitativa Estrutura-Atividade , Ratos , Ratos WistarRESUMO
A series of N-substituted 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ols incorporating the respective arylalkyl subunits from several known sigma (σ) receptor ligands were synthesized and evaluated for their affinity against σ receptors and dopamine receptors. The hybrid trishomocubane-derived ligands (4-6) showed good selectivity for σ(1) and σ(2) receptors over multiple dopamine receptors. The molecular hybrid obtained from haloperidol and 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ol (4, σ(1)K(i)=27 nM, σ(2)K(i)=55 nM) showed reduced affinity for D(1)-D(5) dopamine receptors when compared to haloperidol itself. The compound with the greatest σ(1) affinity in the series, benzamide 4 (σ(1)K(i)=7.6 nM, σ(2)K(i)=225 nM) showed a complete reversal of the subtype selectivity displayed by the highly σ(2) selective parent benzamide, RHM-2 (3, σ(1)K(i)=10412 nM, σ(2)K(i)=13.3 nM).
Assuntos
Alcanos/química , Dodecanol/síntese química , Haloperidol/síntese química , Ligantes , Receptores Dopaminérgicos/metabolismo , Receptores sigma/metabolismo , Alcanos/síntese química , Alcanos/farmacologia , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Ciclização , Dodecanol/química , Dodecanol/farmacologia , Haloperidol/química , Haloperidol/farmacologia , Estrutura Molecular , Especificidade por Substrato/efeitos dos fármacosRESUMO
A series of the cyclopropane-based conformationally restricted analogs of haloperidol were designed as potential antidopaminergic agents and were effectively synthesized using highly stereoselective Grignard reaction with tert-butanesulfinyl imines as the key step. Pharmacological evaluation of the compounds showed that the conformational restriction method can effectively work for improving the pharmacological selectivity of a parent compound and also for investigating the bioactive conformation.
Assuntos
Ciclopropanos/farmacologia , Antagonistas de Dopamina/farmacologia , Desenho de Fármacos , Haloperidol/farmacologia , Piperazinas/farmacologia , Butanos/química , Ciclopropanos/síntese química , Antagonistas de Dopamina/síntese química , Haloperidol/análogos & derivados , Haloperidol/síntese química , Iminas/química , Conformação Molecular , Piperazinas/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Haloperidol (1 a), a dopamine (D(2)) receptor antagonist, is in clinical use as an antipsychotic agent. Carbon/silicon exchange (sila-substitution) at the 4-position of the piperidine ring of 1 a (R(3)COH --> R(3)SiOH) leads to sila-haloperidol (1 b). Sila-haloperidol was synthesized in a new multistep synthesis, starting from tetramethoxysilane and taking advantage of the properties of the 2,4,6-trimethoxyphenyl unit as a unique protecting group for silicon. The pharmacological profiles of the C/Si analogues 1 a and 1 b were studied in competitive receptor binding assays at D(1)-D(5), sigma(1), and sigma(2) receptors. Sila-haloperidol (1 b) exhibits significantly different receptor subtype selectivities from haloperidol (1 a) at both receptor families. The C/Si analogues 1 a and 1 b were also studied for 1) their physicochemical properties (log D, pK(a), solubility in HBSS buffer (pH 7.4)), 2) their permeability in a human Caco-2 model, 3) their pharmacokinetic profiles in human and rat liver microsomes, and 4) their inhibition of the five major cytochrome P450 isoforms. In addition, the major in vitro metabolites of sila-haloperidol (1 b) in human liver microsomes were identified using mass-spectrometric techniques. Due to the special chemical properties of silicon, the metabolic fates of the C/Si analogues 1 a and 1 b are totally different.
Assuntos
Antipsicóticos/farmacologia , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2 , Haloperidol/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Compostos de Organossilício/farmacologia , Antipsicóticos/síntese química , Sítios de Ligação , Sistema Enzimático do Citocromo P-450/metabolismo , Haloperidol/análogos & derivados , Haloperidol/síntese química , Humanos , Concentração Inibidora 50 , Cinética , Microssomos Hepáticos/metabolismo , Compostos de Organossilício/síntese química , Relação Estrutura-AtividadeRESUMO
A novel series of melanin-concentrating hormone (MCH1) receptor antagonists based on combining key fragments from the high-throughput screening (HTS) hits compound 2 (SNAP 7941) and compound 5 (chlorohaloperidol) are described. The resultant analogs, exemplified by compounds 11a-11h, 15a-15h, and 16a-16g, were evaluated in in vitro and in vivo assays for their potential in treatment of mood disorders. From further SAR investigations, N-(3-{1-[4-(3,4-difluorophenoxy)benzyl]-4-piperidinyl}-4-methylphenyl)-2-methylpropanamide (16g, SNAP 94847) was identified to be a high affinity and selective ligand for the MCH1 receptor. Compound 16g also shows good oral bioavailability (59%) and exhibits a brain/plasma ratio of 2.3 in rats. Compound 16g showed in vivo inhibition of a centrally induced MCH-induced drinking effect and exhibited a dose-dependent anxiolytic effect in the rat social interaction model.
Assuntos
Ansiolíticos/síntese química , Proteínas do Citoesqueleto/antagonistas & inibidores , Haloperidol/análogos & derivados , Piperidinas/síntese química , Animais , Ansiolíticos/farmacocinética , Ansiolíticos/farmacologia , Ansiedade/psicologia , Disponibilidade Biológica , Encéfalo/metabolismo , Linhagem Celular , Proteínas do Citoesqueleto/metabolismo , Ingestão de Líquidos/efeitos dos fármacos , Haloperidol/síntese química , Haloperidol/farmacocinética , Haloperidol/farmacologia , Humanos , Ligantes , Masculino , Atividade Motora/efeitos dos fármacos , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Comportamento SocialRESUMO
Methods are presented to synthesize and characterize [methylene-3H] haloperidol 2 and [N-methyl-3H]trifluoperazine 6.
Assuntos
Antipsicóticos/síntese química , Haloperidol/síntese química , Trifluoperazina/síntese química , Trítio/química , Haloperidol/análogos & derivados , Espectroscopia de Ressonância MagnéticaRESUMO
Enantiomeric separation of the racemic 4-{3-(4-chlorophenyl)-3-hydroxypyrrolidin-1-yl}-1-(4-fluorophenyl)butan-1-one, a pyrrolidine analog of haloperidol, {(+/-)-SYA 09}, and subsequent binding studies revealed that most of the binding affinity at dopamine and serotonin receptors resides in the (+)-isomer {(+)-SYA 09} or the eutomer. Further pharmacological evaluation of the eutomer revealed that it has a higher affinity for the dopamine D4 (DAD4) receptor subtype (Ki = 3.6 nM) than for the DAD2 subtype (Ki = 51.1 nM) with a ratio of 14.2 (D2Ki/D4Ki ratio = 14.2). In an animal model of antipsychotic efficacy, the (+)-SYA 09 was efficacious with an ED50 value of 1.6 mg/kg, i.p., and at twice this value, (+)-SYA 09 did not induce significant catalepsy in rats.
Assuntos
Butanonas/síntese química , Haloperidol/análogos & derivados , Haloperidol/farmacologia , Pirrolidinas/síntese química , Animais , Butanonas/química , Butanonas/farmacologia , Clozapina/química , Clozapina/farmacologia , Haloperidol/síntese química , Haloperidol/química , Humanos , Isomerismo , Camundongos , Estrutura Molecular , Pirrolidinas/química , Pirrolidinas/farmacologia , RatosRESUMO
A series of 3-aminoethyl-1-tetralones, conformationally constrained higher homologues of haloperidol (standard for typical antipsychotic profile), have been obtained by a four-step route from valerolactone. Their binding affinities at dopamine D(2) and serotonin 5-HT2A and 5-HT2C receptors were determined, showing in some cases an atypical antipsychotic profile.
Assuntos
Antipsicóticos/síntese química , Antipsicóticos/metabolismo , Haloperidol/síntese química , Haloperidol/metabolismo , Tetralonas/síntese química , Tetralonas/metabolismo , Sítios de Ligação , Haloperidol/análogos & derivados , Receptores de Dopamina D2/metabolismo , Receptores 5-HT2 de Serotonina/metabolismoRESUMO
The long-term, irreversible, Parkinsonism-like side effects of haloperidol have been speculated to involve several mechanisms. More recently, it has been speculated that the metabolic transformation to MPP+-like species may contribute to the Parkinsonism-like side effects. Because BCPP+ and its reduced analogue have been shown to possess the potential to destroy dopamine receptors in the nigrostriatum, we have designed new analogues of haloperidol lacking the structural features necessary to form neurotoxic quaternary species but retaining their dopamine-binding capacity. The most potent agent at the D2 receptor, the homopiperidine analogue 11, was found to be equipotent to haloperidol. It was also of interest to identify analogues with DA binding profiles similar to that of clozapine at the dopamine receptor subtypes. Evaluation of the proposed agents shows that the ratio of D2 to D4 (2) binding of clozapine was mimicked by 7 [K(i)(D2) = 33, K(i)(D3) = 200, K(i)(D4) = 11 nM; K(i)(D2)/K(i)(D4) = 3] and 9 [K(i)(D2) = 44, K(i)(D3) = 170, K(i)(D4) = 24 nM; K(i)(D2)/K(i)(D4) = 2]. A preliminary in-vivo testing of compound 7 shows that its behavioral profile is similar to that of clozapine. This profile suggests that there is a need for further evaluation of these two synthetic agents and their enantiomers for efficacy and lack of catalepsy in animal models.
Assuntos
Azepinas/síntese química , Haloperidol/análogos & derivados , Haloperidol/síntese química , Animais , Azepinas/química , Azepinas/farmacologia , Catalepsia/induzido quimicamente , Clozapina/farmacologia , Desenho de Fármacos , Haloperidol/química , Haloperidol/metabolismo , Haloperidol/farmacologia , Humanos , Técnicas In Vitro , Masculino , Camundongos , Piperidinas/metabolismo , Compostos de Amônio Quaternário/metabolismo , Ensaio Radioligante , Ratos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D4 , Estereoisomerismo , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A series of (R)- and (S)-3-aminomethyl-1-tetralones, conformationally constrained analogues of haloperidol, have been obtained by enzymatic resolution of the corresponding racemic 3-hydroxymethyl-1-tetralones using Pseudomonas fluorescens lipase. Their binding affinities at dopamine D(2) and serotonin 5-HT(2A) and 5-HT(2C) receptors were determined showing in some cases an atypical antipsychotic profile with Meltzer's ratio higher than 1.30.