Novel Antipsychotic Agents with Dopamine Autoreceptor Agonist Properties:  Synthesis and Pharmacology of 7-[4-(4-Phenyl-1-piperazinyl)butoxy]-3,4-dihydro-2(1H)-quinolinone Derivatives

Abstract

To develop a novel antipsychotic agent which is an agonist of dopamine (DA) autoreceptors and an antagonist of postsynaptic DA receptors, a series of 7-[4-[4-(substituted phenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2 (1H)-quinolinones was synthesized and their dual activities were examined. The postsynaptic DA receptor antagonistic activities of the compounds were evaluated by their ability to inhibit stereotypy induced by apomorphine in mice, and the autoreceptor agonist activities were determined by their effects on the gamma-butyrolactone (GBL)-induced increase in L-dihydroxyphenylalanine (DOPA) synthesis in the mouse brain. Many compounds inhibited the stereotypic behavior, and several compounds reversed the GBL-induced increase in the DOPA synthesis. Among them, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy]-3,4-dihydro-2 (1H)-quinolinone (28, aripiprazole, OPC-14597) was found to have these two activities. This compound reversed the GBL-induced DOPA synthesis (ED50 values of 5.1 mumol/kg p.o.) and inhibited the APO induced stereotypy (ED50 values of 0.6 mumol/kg p.o.). Compound 28 induced catalepsy at 10 times higher dose than that required for the antagonism of APO-induced stereotypy (ED50 value of 7.8 mumol/kg p.o.).

Histidine 6.55 Is a Major Determinant of Ligand-Biased Signaling in Dopamine D2LReceptor

“…Dopamine (3,4-dihydroxyphenethylamine), quinpirole [(Ϫ)-quinpirole hydrochloride], spiperone, haloperidol, 7-hydroxy-2-(N,N-di-n-propylamino)tetralin (7-OH-DPAT), and other compounds were purchased from Sigma, unless otherwise stated. The compounds FAUC335 (Ehrlich et al, 2009), N-[3-[4-(2-methoxyphenyl) (Bettinetti et al, 2002), N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)biphenyl-4-carboxamide (CPD1) (Hackling et al, 2003), N-[4-[4-(2-methoxyphenyl) (Bettinetti et al, 2002), and aripiprazole (Oshiro et al, 1998) were synthesized as described previously. See Fig.…”

Aripiprazole: A Novel Atypical Antipsychotic Drug With a Uniquely Robust Pharmacology

“…Data from binding studies consistently indicate that aripiprazole has a high affinity for dopamine D 2 (15,49,54,80) and D 3 (15,54,80) receptors, a moderate affinity for D 4 receptors (54,60) and low affinity for D 1 Functionally, aripiprazole has demonstrated both agonist and antagonist properties at the D 2 receptor, which fits a partial agonist pharmacologic profile (2,50,55,66,87). While aripiprazole has high affinity for D 2 receptors, it has low intrinsic efficacy (15,89).…”

Aripiprazole, A Novel Atypical Antipsychotic Drug with a Unique and Robust Pharmacology

“…Recently, the FDA approved aripiprazole, a new atypical antipsychotic drug (Inoue et al, 1997;Inoue et al, 1996;Oshiro et al, 1998) that is proposed to differ in mechanism of action from other atypical antipsychotic drugs. Aripiprazole has high affinity for D 2 -and D 3 -dopamine and 5-HT 7 serotonin receptors (Lawler et al, 1999).…”