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1.
J Med Chem ; 51(15): 4780-9, 2008 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-18598020

RESUMO

A new series of quinazolinone derivatives was synthesized and evaluated as nonimidazole H 3 receptor inverse agonists. 2-Methyl-3-(4-[[3-(1-pyrrolidinyl)propyl]oxy]phenyl)-5-(trifluoromethyl)-4(3 H)-quinazolinone ( 1) was identified as a promising derivative for further evaluation following optimization of key parameters. Compound 1 has potent H 3 inverse agonist activity and excellent selectivity over other histamine receptor subtypes and a panel of 115 unrelated diverse binding sites. Compound 1 also shows satisfactory pharmacokinetic profiles and brain penetrability in laboratory animals. Two hours after oral administration of 30 mg/kg of 1 to SD rats, significant elevation of brain histamine levels was observed where the brain H 3 receptor was highly occupied (>90%). On the basis of species differences in P-glycoprotein (P-gp) susceptibility of 1 between human and rodent P-gps, the observed rodent brain permeability of 1 is significantly limited by P-gp mediated efflux in rodents, whereas the extent of P-gp mediated efflux in humans should be very small or negligible. The potential of 1 to be an efficacious drug was demonstrated by its excellent brain penetrability and receptor occupancy in P-gp-deficient CF-1 mice.


Assuntos
Agonistas dos Receptores Histamínicos/síntese química , Agonistas dos Receptores Histamínicos/farmacologia , Quinazolinonas/síntese química , Quinazolinonas/farmacologia , Aminas/química , Animais , Linhagem Celular , Agonistas dos Receptores Histamínicos/química , Agonistas dos Receptores Histamínicos/classificação , Antagonistas dos Receptores Histamínicos/química , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estrutura Molecular , Quinazolinonas/química , Quinazolinonas/classificação , Receptores Histamínicos H3/metabolismo , Relação Estrutura-Atividade
2.
J Clin Pharm Ther ; 29(3): 279-98, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15153091

RESUMO

BACKGROUND: From the deductive point of view, neurotransmitter receptors can be divided into categories such as cholinergic (muscarinic, nicotinic), adrenergic (alpha- and beta-), dopaminergic, serotoninergic (5-HT1 approximately 5-HT5), and histaminergic (H1 and H2). Selective agonists and antagonists of each receptor subtype can have specific useful therapeutic applications. For understanding the molecular mechanisms of action, an inductive method of analysis is useful. OBJECTIVE: The aim of the present study is to examine the structure-activity relationships of agents acting on G-protein coupled receptors. METHOD: Representative sets of G-PCR agonists and antagonists were identified from the literature and Medline [P.M. Walsh (2003) Physicians' Desk Reference; M.J. O'Neil (2001) The Merck Index]. The molecular weight (MW), calculated logarithm of octanol/water partition coefficient (C log P) and molar refraction (CMR), dipole moment (DM), E(lumo) (the energy of the lowest unoccupied molecular orbital, a measure of the electron affinity of a molecule and its reactivity as an electrophile), E(homo) (the energy of the highest occupied molecular orbital, related to the ionization potential of a molecule, and its reactivity as a nucleophile), and the total number of hydrogen bonds (H(b)) (donors and receptors), were chosen as molecular descriptors for SAR analyses. RESULTS: The data suggest that not only do neurotransmitters share common structural features but their receptors belong to the same ensemble of G-protein coupled receptor with seven to eight transmembrane domains with their resultant dipoles in an antiparallel configuration. Moreover, the analysis indicates that the receptor exists in a dynamic equilibrium between the closed state and the open state. The energy needed to open the closed state is provided by the hydrolysis of GTP. A composite 3-D parameter frame setting of all the neurotransmitter agonists and antagonists are presented using MW, Hb and mu as independent variables. CONCLUSION: It appears that all neurotransmitters examined in this study operate by a similar mechanism with the G-protein coupled receptors.


Assuntos
Neurotransmissores/antagonistas & inibidores , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Acoplados a Proteínas G/fisiologia , Relação Estrutura-Atividade , Agonistas Adrenérgicos/química , Agonistas Adrenérgicos/classificação , Antagonistas Adrenérgicos/química , Antagonistas Adrenérgicos/classificação , Fenômenos Químicos , Físico-Química , Agonistas Colinérgicos/química , Agonistas Colinérgicos/classificação , Antagonistas Colinérgicos/química , Antagonistas Colinérgicos/classificação , Agonistas de Dopamina/química , Agonistas de Dopamina/classificação , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/química , Antagonistas de Dopamina/classificação , Antagonistas de Dopamina/farmacologia , Agonistas dos Receptores Histamínicos/química , Agonistas dos Receptores Histamínicos/classificação , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/classificação , Antagonistas dos Receptores Histamínicos/farmacologia , Modelos Biológicos , Estrutura Molecular , Neurotransmissores/agonistas , Neurotransmissores/química , Receptores Adrenérgicos/classificação , Receptores Adrenérgicos/efeitos dos fármacos , Receptores Adrenérgicos/fisiologia , Receptores Colinérgicos/classificação , Receptores Colinérgicos/efeitos dos fármacos , Receptores Colinérgicos/fisiologia , Receptores Histamínicos/classificação , Receptores Histamínicos/efeitos dos fármacos , Receptores Histamínicos/fisiologia , Antagonistas da Serotonina/química , Antagonistas da Serotonina/classificação , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/classificação , Agonistas do Receptor de Serotonina/farmacologia
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