RESUMO
Starting from the tetrahydroisoquinoline SB-277011 1, a novel series of 5-substituted-2,3-dihydro-1H-isoindoles has been designed. Subsequent optimisation resulted in identification of 19, which has high affinity for the dopamine D3 receptor (pKi 8.3) and > or = 100-fold selectivity over other aminergic receptors. In rat studies 19 was brain penetrant with an excellent pharmacokinetic profile (oral bioavailability 77%, t1/2 5.2h).
Assuntos
Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Indóis/química , Indóis/farmacologia , Receptores de Dopamina D2/metabolismo , Animais , Encéfalo/metabolismo , Células CHO , Cricetinae , Antagonistas de Dopamina/síntese química , Antagonistas de Dopamina/metabolismo , Desenho de Fármacos , Humanos , Indóis/síntese química , Indóis/metabolismo , Modelos Moleculares , Estrutura Molecular , Ensaio Radioligante , Ratos , Receptores de Dopamina D3RESUMO
Starting from the dopamine D3 receptor antagonist SB-277011 1, a series of 2,3,4,5-tetrahydro-1H-3-benzazepines has been identified with high affinity for the dopamine D3 receptor and selectivity over the D2 receptor. The 3-acetamido-2-fluorocinnamide derivative 20 gave high D3 receptor affinity (pKi 8.4) with 130-fold selectivity over the 2, receptor.
Assuntos
Nitrilas/farmacologia , Quinolinas/farmacologia , Receptores de Dopamina D2/efeitos dos fármacos , Tetra-Hidroisoquinolinas , Animais , Nitrilas/química , Quinolinas/química , Ratos , Receptores de Dopamina D3RESUMO
SB-277011-A (trans-N-[4-[2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide), is a brain-penetrant, high-affinity, and selective dopamine D(3) receptor antagonist. Radioligand-binding experiments in Chinese hamster ovary (CHO) cells transfected with human dopamine D(3) or D(2 long) (hD(3), hD(2)) receptors showed SB-277011-A to have high affinity for the hD(3) receptor (pK(i) = 7.95) with 100-fold selectivity over the hD(2) receptor and over 66 other receptors, enzymes, and ion channels. Similar radioligand-binding data for SB-277011-A were obtained from CHO cells transfected with rat dopamine D(3) or D(2). In the microphysiometer functional assay, SB-277011-A antagonized quinpirole-induced increases in acidification in CHO cells overexpressing the hD(3) receptor (pK(b) = 8.3) and was 80-fold selective over hD(2) receptors. Central nervous system penetration studies showed that SB-277011-A readily entered the brain. In in vivo microdialysis studies, SB-277011-A (2. 8 mg/kg p.o.) reversed the quinelorane-induced reduction of dopamine efflux in the nucleus accumbens but not striatum, a regional selectivity consistent with the distribution of the dopamine D(3) receptor in rat brain. SB-277011-A (2-42.3 mg/kg p.o.) did not affect spontaneous locomotion, or stimulant-induced hyperlocomotion. SB-277011-A (4.1-42.2 mg/kg p.o.) did not reverse prepulse inhibition deficits in apomorphine- or quinpirole-treated rats, but did significantly reverse the prepulse inhibition deficit in isolation-reared rats at a dose of 3 mg/kg p.o. SB-277011-A (2.5-78. 8 mg/kg p.o.) was noncataleptogenic and did not raise plasma prolactin levels. Thus, dopamine D(3) receptor blockade produces few of the behavioral effects characteristic of nonselective dopamine receptor antagonists. The effect of SB-277011-A on isolation-induced prepulse inhibition deficit suggests that blockade of dopamine D(3) receptors may benefit the treatment of schizophrenia.
Assuntos
Antagonistas de Dopamina/farmacologia , Nitrilas/farmacologia , Quinolinas/farmacologia , Receptores de Dopamina D2/efeitos dos fármacos , Tetra-Hidroisoquinolinas , Animais , Encéfalo/metabolismo , Células CHO , Catalepsia/induzido quimicamente , Cricetinae , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/toxicidade , Humanos , Masculino , Microdiálise , Atividade Motora/efeitos dos fármacos , Nitrilas/metabolismo , Nitrilas/toxicidade , Prolactina/sangue , Quinolinas/metabolismo , Quinolinas/toxicidade , Ensaio Radioligante , Ratos , Ratos Endogâmicos , Ratos Sprague-Dawley , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3 , Reflexo de Sobressalto/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , TransfecçãoRESUMO
A selective dopamine D(3) receptor antagonist offers the potential for an effective antipsychotic therapy, free of the serious side effects of currently available drugs. Using clearance and brain penetration studies as a screen, a series of 1,2,3, 4-tetrahydroisoquinolines, exemplified by 13, was identified with high D(3) affinity and selectivity against the D(2) receptor. Following examination of molecular models, the flexible butyl linker present in 13 was replaced by a more conformationally constrained cyclohexylethyl linker, leading to compounds with improved oral bioavailability and selectivity over other receptors. Subsequent optimization of this new series to improve the cytochrome P450 inhibitory profile and CNS penetration gave trans-N-[4-[2-(6-cyano-1, 2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarbo xamide (24, SB-277011). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and brain penetration in the rat and represents an excellent new chemical tool for the investigation of the role of the dopamine D(3) receptor in the CNS.
Assuntos
Sistema Nervoso Central/metabolismo , Antagonistas de Dopamina/síntese química , Nitrilas/síntese química , Quinolinas/síntese química , Receptores de Dopamina D2/efeitos dos fármacos , Tetra-Hidroisoquinolinas , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Catalepsia/induzido quimicamente , Catalepsia/psicologia , Sistema Nervoso Central/efeitos dos fármacos , Cricetinae , Antagonistas de Dopamina/farmacocinética , Antagonistas de Dopamina/farmacologia , Meia-Vida , Humanos , Masculino , Microdiálise , Nitrilas/farmacocinética , Nitrilas/farmacologia , Prolactina/sangue , Quinolinas/farmacocinética , Quinolinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D3RESUMO
Using clearance and brain penetration studies as a screen, tetrahydroisoquinoline 3 was identified as a lead having low clearance in rats (CLb 20 ml/min/kg). Introduction of a 7-CF3SO2O- substituent into the tetrahydroisoquinoline, followed by replacement of the biphenylamido group of 3 by a 3-indolylpropenamido group gave 31, having high D3 receptor affinity (pKi 8.4) and 150 fold selectivity over the D2 receptor.
Assuntos
Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Receptores de Dopamina D2/química , Animais , Encéfalo/efeitos dos fármacos , Isoquinolinas/administração & dosagem , Isoquinolinas/sangue , Modelos Moleculares , Ratos , Receptores de Dopamina D3RESUMO
A model series of 5-HT2C antagonists have been prepared by rapid parallel synthesis. These N-substituted phenyl-N'-pyridin-3-yl ureas were found to have a range of 5-HT2C receptor affinities and selectivities over the closely related 5-HT2A receptor. Extrapolation of simple SAR, derived from this set of compounds, to the more active but synthetically more complex 1-(3-pyridylcarbamoyl)indoline series allowed us to target optimal substitution patterns and identify potent and selective 5-HT(2C/2B) antagonists.
Assuntos
Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Piridinas/química , Piridinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Animais , Humanos , Técnicas In Vitro , Cinética , Espectroscopia de Ressonância Magnética , Modelos Químicos , Compostos de Fenilureia/síntese química , Piridinas/síntese química , Receptor 5-HT2B de Serotonina , Receptor 5-HT2C de Serotonina , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/síntese química , Relação Estrutura-AtividadeRESUMO
The synthesis, biological activity, and molecular modeling of a novel series of substituted 1-(3-pyridylcarbamoyl)indolines are reported. These compounds are isosteres of the previously published indole urea 1 (SB-206553) and illustrate the use of aromatic disubstitution as a replacement for fused five-membered rings in the context of 5-HT2C/2B receptor antagonists. By targeting a region of space previously identified as sterically allowed at the 5-HT2C receptor but disallowed at the 5-HT2A receptor, we have identified a number of compounds which are the most potent and selective 5-HT2C/2B receptor antagonists yet reported. 46 (SB-221284) was selected on the basis of its overall biological profile for further evaluation as a novel, potential nonsedating anxiolytic agent. A CoMFA analysis of these compounds produced a model with good predictive value and in addition good qualitative agreement with both our 5-HT2C receptor model and our proposed binding mode for this class of ligands within that model.
Assuntos
Ansiolíticos , Indóis , Modelos Moleculares , Piridinas , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Ansiolíticos/metabolismo , Ansiolíticos/farmacologia , Condicionamento Operante/efeitos dos fármacos , Conflito Psicológico , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Piridinas/síntese química , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2B de Serotonina , Receptor 5-HT2C de Serotonina , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Antagonistas da Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Comportamento Social , Relação Estrutura-AtividadeRESUMO
Starting from a series of 2-aminotetralins 1, a novel series of N-[4-(4-phenylbenzoylamino)butyl]-octahydrobenzoquinolines and hexahydrobenzoindoles with high potency and selectivity for the dopamine D3 receptor has been designed. The effect of ligand chirality on binding affinity has been established. Selected derivatives (e.g. 2o, 2p) show high functional selectivity and enhanced in vivo properties compared to 1.