RESUMO
SCH 23390 is a novel benzazepine that selectively blocks dopamine receptors of the D1 subtype. Glucuronidation of this selective D1 antagonist was studied in vitro using rat liver microsomes. Methods to separate SCH 23390 glucuronide from SCH 23390 were developed which utilized either HPLC techniques or solvent extraction of SCH 23390 with 3-heptanone. Formation of a SCH 23390 glucuronide was confirmed upon incubation of SCH 23390 and UDPGA with naive rat liver microsomes. Liver enzyme activity for SCH 23390 glucuronidation was also enhanced after addition of the detergents, Lubrol or Triton X-100, to the naive liver microsomes. Kinetic analyses indicated an apparent Vmax and Km for UDPGA as 120.9 pmol/mg protein/min and 0.63 mM, and an apparent Vmax and Km for SCH 23390 as 282.4 pmol/mg protein/min and 0.41 microM. Further characterization of the liver enzyme responsible for the glucuronidation of SCH 23390 revealed a stereoselective substrate preference similar to that seen with the D1 dopamine receptor. Substrate inhibition studies indicated that SCH 23390, haloperidol, apomorphine, and alpha-naphthol demonstrated the highest affinity for the glucuronosyltransferase enzyme. However, (-)-sulpiride, raclopride, and endogenous substrates such as dopamine, serotonin, epinephrine, and norepinephrine demonstrated low affinity for the liver enzyme. These studies describe a rat liver glucuronosyltransferase with a unique substrate specificity toward selected dopaminergic agents. Finally, induction profiles revealed that neither phenobarbital (100 mg/kg, ip, for 3 days), beta-naphthoflavone (100 mg/kg, ip, for 4 days), nor 3-methylcholanthrene (80 mg/kg, ip, for 4 days) enhanced liver glucuronosyltransferase activity for SCH 23390 glucuronidation.
Assuntos
Benzazepinas/metabolismo , Glucuronosiltransferase/metabolismo , Fígado/enzimologia , Animais , Indução Enzimática , Glucuronatos/metabolismo , Glucuronidase/metabolismo , Glucuronosiltransferase/biossíntese , Cinética , Masculino , Microssomos Hepáticos/enzimologia , Ratos , Ratos Endogâmicos , Relação Estrutura-Atividade , Especificidade por Substrato , TrítioRESUMO
Structure activity studies on [4-(phenylsulfonyl)phenyl]methylpiperazine led to the discovery of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl(S)-sufinyl]phenyl]-1-pi perazineacetonitrile, 1, an M2 selective muscarinic antagonist. Affinity at the cloned human M2 receptor was 2.7 nM; the M1/M2 selectivity is 40-fold.
Assuntos
Derivados de Benzeno/síntese química , Antagonistas Muscarínicos/síntese química , Receptores Muscarínicos/efeitos dos fármacos , Acetilcolina/metabolismo , Administração Oral , Alcaloides/química , Alcaloides/farmacologia , Animais , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dibenzazepinas/química , Dibenzazepinas/farmacologia , Desenho de Fármacos , Furanos , Humanos , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacologia , Naftalenos , Piperidinas , Piridinas/química , Piridinas/farmacologia , Ratos , Receptor Muscarínico M2 , Receptores Muscarínicos/fisiologia , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Piperidine analogues of our previously described piperazine muscarinic antagonists are described. Piperidine analogues show a distinct structure-activity relationship (SAR) that differs from comparable piperazines. Compounds with high selectivity and improved potency for the M2 receptor have been identified. The lead compound, 12b, increases acetylcholine release in vivo. Compounds of this class may be useful for the treatment of cognitive disorders such as Alzheimer's disease (AD).