Chloro-substituted, sterically hindered 5,11-dicarbo analogues of clozapine as potential chiral antipsychotic agents

Variable-temperature proton nuclear magnetic resonance studies have shown that 5-(2-propylidene)-10-(4-methylpiperazino)-5H-dibenzo[a,d] cycloheptene, a 5,11-dicarbo analogue of the atypical neuroleptic agent clozapine [8-chloro-11-(4-methylpiperazino)-5H-dibenzo[b,e][1,4]diazepine], exists as thermally stable configurational isomers. The presence of the 2-propylidene group at C-5 on the 5H-dibenzo[a,d]cycloheptene moiety did not interfere greatly, as compared to clozapine, with the in vitro affinity of this 5,11-dicarbo analogue of clozapine for muscarinic and dopamine D-1 and D-2 binding sites in rat brain. Since the presence and position of a chloro substituent on the 5H-dibenzo[b,e][1,4]diazepine moiety have a marked influence on the respective binding affinities of 1,4-diazepines related to clozapine, chloro-substituted 5,11-dicarbo analogues of clozapine were prepared in order to further examine structure-activity relationships. Evaluation of these analogues for binding to muscarinic and dopamine binding sites in comparison with clozapine and other 5H-dibenzo[b,e][1,4]diazepine analogues of clozapine shows that the dopamine D-1 and D-2 receptor affinities of both the 5-(2-propylidene)-5,11-dicarbo analogue and its corresponding distal-chloro derivative, 2-chloro-5-(2-propylidene)-10-(4-methylpiperazino)-5H- dibenzo[a,d]cycloheptene, are retained. Because of the susceptibility to acid-catalyzed hydrolysis of these tertiary enamines, however, these compounds serve only as model compounds for their structure-activity evaluation. Since the proximal nitrogen atom of the piperazine ring is redundant for biological activity, 5-(2-propylidene)-10-(1-methyl-4-pyridyl)-5H-dibenzo[a,d]cycloh eptene and its 2-chloro derivative are excellent candidates for resolution into enantiomers as a means to separate antimuscarinic and antidopaminergic activity, respectively, associated with only a single stereoisomer.     

Synthesis, structure-activity relationships, and biological properties of 1-heteroaryl-4-[omega-(1H-indol-3-yl)alkyl]piperazines, novel potential antipsychotics combining potent dopamine D2 receptor antagonism with potent serotonin reuptake inhibition

A series of novel bicyclic 1-heteroaryl-4-[omega-(1H-indol-3-yl)alkyl]piperazines was synthesized and evaluated on binding to dopamine D(2) receptors and serotonin reuptake sites. This class of compounds proved to be potent in vitro dopamine D(2) receptor antagonists and in addition were highly active as serotonin reuptake inhibitors. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both the antagonism of apomorphine-induced climbing and the potentiation of 5-HTP-induced behavior in mice. On the basis of the preclinical data, 8-{4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazin-1-yl}-4H-benzo[1,4]oxazin-(R)-2-methyl-3-one (45c, SLV314) was selected for clinical development. In vitro and in vivo studies revealed that 45c has favorable pharmacokinetic properties and a high CNS-plasma ratio. Molecular modeling studies showed that the bifunctional activity of 45c can be explained by its ability to adopt two different conformations fitting either the dopamine D(2) receptor pharmacophore or the serotonin transporter pharmacophore.     

Identification, isolation, synthesis and characterization of impurities of quetiapine fumarate

In the process for the preparation of quetiapine fumarate (1), six unknown impurities and one known impurity (intermediate) were identified ranging from 0.05-0.15% by reverse-phase HPLC. These impurities were isolated from crude samples using reverse-phase preparative HPLC. Based on the spectral data, the impurities were characterized as 2-[4-dibenzo[b,f][1,4]thiazepine-11-yl-1 -piperazinyl]1 -2-ethanol (impurity I, desethanol quetiapine), 11-[(N-formyl)-1-piperazinyl]-dibenzo[b,f][1,4]thiazepine (impurity II, N-formyl piperazinyl thiazepine), 2-(2-hydroxy ethoxy)ethyl-2-[2-[4-dibenzo[b,f][1,4]thiazepine-11- piperazinyl-1-carboxylate (impurity III, quetiapine carboxylate), 11-[4-ethyl-1-piperazinyl]dibenzo [b,f][1,4] thiazepine (impurity IV, ethylpiperazinyl thiazepine), 2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]1-ethyl ethanol [impurity V, ethyl quetiapine), 1,4-bis[dibenzo[b,f][1,4]thiazepine-11-yl] piperazine [impurity VI, bis(dibenzo)piperazine]. The known impurity was an intermediate, 11-piperazinyldibenzo [b,f][1,4]thiazepine (piperazinyl thiazepine). The structures were established unambiguously by independent synthesis and co-injection in HPLC to confirm the retention times. To the best of our knowledge, these impurities have not been reported before. Structural elucidation of all impurities by spectral data (1H NMR, 13C NMR, MS and IR), synthesis and formation of these impurities are discussed in detail.     

Microwave-assisted solvent-free synthesis of 3-[(4-substituted piperazin-1-yl)alkyl] imidazo[2,1-b][1,3]benzothiazol-2(3H)-ones as serotonin3 (5-HT3) receptor antagonists

A series of novel 3-[(4-substituted piperazin-1-yl)alkyl]imidazo[2,1-b][1,3]benzothiazol-2(3H)-ones were prepared by microwave irradiation using alumina as solid support and also by a conventional method. The compounds were characterized by spectral data and the purity was ascertained by microanalysis. The synthesized compounds were evaluated for 5-hydroxytryptamine3 antagonisms in a longitudinal muscle-myenteric plexus preparation from guinea pig ileum against the 5-hydroxytryptamine3 agonist, 2-methyl-5-hydroxytryptamine. Among the test compounds, 3-[2-(4-methylpiperazin-1-yl)ethyl]imidazo[2,1-b][1,3]benzothiazol-2(3H)-one (3b) showed most favorable 5-hydroxytryptamine3 antagonism (pA2 6.7) in the isolated guinea pig ileum.     

New 3-[4-(2,3-dihydro-14-benzodioxin-5-yl)piperazin-1-yl]-1-(5-substituted benzo[b]thiophen-3-yl)propanol derivatives with dual action at 5-HT(1A) serotonin receptors and serotonin transporter as a new class of antidepressants

Compounds derived from 2,3-dihydro-(1,4-benzodioxin-5-yl)piperazine and benzo[b]thiophene with different substituents in 5 position (H, F, NO2, NH2, CH3 and OH) have been synthesized in order to obtain new dual antidepressant drugs. The final compounds were evaluated for in vitro 5-HT(1A) receptor affinity and serotonin reuptake inhibition by radioligand assays. Compounds 1-(5-nitrobenzo[b]thiophen-3-yl)-3-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]propan-1-ol (4c) (Ki = 6.8 for 5-HT(1A) receptor and Ki = 14 for 5-HT transporter) and 1-(5-hydroxybenzo[b]thiophen-3-yl)-3-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl] propan-1-ol (4f) (Ki = 6.2 for 5-HT(1A) receptor and Ki = 18.2 for 5-HT transporter) showed the best results for both activities.     

Partial agonist properties of the antipsychotics SSR181507, aripiprazole and bifeprunox at dopamine D2 receptors: G protein activation and prolactin release

Dopamine D2 receptor antagonists induce hyperprolactinemia depending on the extent of D2 receptor blockade. We compared the effects of the new antipsychotic agents SSR181507 ((3-exo)-8-benzoyl-N-[[(2 s)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride), bifeprunox (DU127090: 1-(2-Oxo-benzoxazolin-7-yl)-4-(3-biphenyl)methylpiperazinemesylate) and SLV313 (1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-piperazine) with those of aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butyloxy)-3,4-dihydro-2(1 H)-quinolinone), clozapine and haloperidol, on functional measures of dopamine D2 receptor activity in vitro and in vivo: [35S]-GTPgammaS binding to membranes from Sf9 insect cells expressing human dopamine D2 Long (hD2 L) receptors, and serum prolactin levels in the rat. All compounds antagonized apomorphine-induced G protein activation at dopamine hD2 L receptors. Antagonist potencies of aripiprazole, bifeprunox and SLV313 were similar to haloperidol (pK(b) = 9.12), whereas SSR181507 (8.16) and clozapine (7.35) were less potent. Haloperidol, SLV313 and clozapine were silent antagonists but SSR181507, bifeprunox and aripiprazole stimulated [35S]-GTPgammaS binding by 17.5%, 26.3% and 25.6%, respectively, relative to 100 microM apomorphine (Emax = 100%). pEC50s were: SSR181507, 8.08; bifeprunox, 8.97; aripiprazole, 8.56. These effects were antagonized by raclopride. Following oral administration in vivo, the drugs increased prolactin release to different extents. SLV313 and haloperidol potently (ED50 0.12 and 0.22 mg/kg p.o., respectively) stimulated prolactin release up to 86 and 83 ng/ml. Aripiprazole potently (ED50 0.66 mg/kg p.o.) but partially (32 ng/ml) induced prolactin release. SSR181507 (ED50 4.9 mg/kg p.o.) also partially (23 ng/ml) enhanced prolactin release. Bifeprunox only weakly increased prolactin at high doses (13 ng/ml at 40 mg/kg) and clozapine only affected prolactin at the highest dose tested (41 ng/ml at 40 mg/kg). Prolactin levels of the corresponding vehicle-treated animals were <4.3 ng/ml. These data show that (1) SSR181507, aripiprazole and bifeprunox, but not SLV313, are partial agonists at dopamine hD2 L receptors in vitro; (2) SSR181507, bifeprunox and aripiprazole exhibit reduced prolactin release in vivo compared with drugs that are neutral antagonists at dopamine D2 receptors.     

Characterization of the histamine H4 receptor binding site. Part 1. Synthesis and pharmacological evaluation of dibenzodiazepine derivatives

A series of dibenzodiazepine derivatives was synthesized to probe the binding site of the recently discovered histamine H4 receptor (H4R). Optimization of the lead structure clozapine (2) resulted in (E)-7-chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine (7j), a potent H4R agonist (H4R, pKi = 7.6). Pharmacological data suggests that the series of nonimidazole compounds can be used to describe the orthosteric binding site of the H4R because both 2 and 7j displace [3H]histamine in a competitive manner. Furthermore, it is demonstrated that the effects of 7j are competitively antagonized by the selective H4R antagonist JNJ 7777120 (1), indicating considerable overlap of their binding sites. On the basis of the derived structure-activity relationships and additional pharmacological results, a pharmacophore model was constructed, which will be the premise for the design of novel H4R ligands.     

Antidyskinetic effect of JL-18, a clozapine analog, in parkinsonian monkeys

Clozapine reduces L-3,4-dihydroxyphenylalanine (L-Dopa)-induced dyskinesias in parkinsonian patients. To test if the antidyskinetic effect of clozapine is related to antagonism at the dopamine D(4) receptor, we investigated the effect of 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1, 4]benzodiazepine (JL-18), a structural analog of clozapine which is more selective for this receptor. Four 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias to L-Dopa were used in this study. They were injected subcutaneously (s.c.) with L-Dopa methyl ester (125 mg per animal) plus benserazide (50 mg per animal; L-Dopa/benserazide) alone or in combination with JL-18 (at the doses of 0.1, 0.3, or 0.9 mg/kg, s.c.). Subcutaneous injection of sterile saline was used as control. L-Dopa/benserazide increased locomotion and improved parkinsonism but also induced dyskinesias. Co-administration of JL-18, at low doses (0.1, 0.3 mg/kg) with L-Dopa/benserazide, produced a dose-dependent reduction in L-Dopa-induced dyskinesias without a parallel return to parkinsonism. The present results suggest that novel selective dopamine D(4) receptor antagonists may represent a useful tool to reduce L-Dopa-induced dyskinesias.     

Synthesis of new 2-(aminomethyl)-4-phenylpyrrolo[1,2-a]-quinoxalines and their preliminary in-vivo central dopamine antagonist activity evaluation in mice

In the search for antipsychotic agents that are not associated with extrapyramidal side effects, efforts have been focused on finding selective D4-receptor antagonists and investigating their pharmacology. Our laboratory has developed a synthesis program for new pyrroloquinoxalines with therapeutic potential. We have described the synthesis of some new pyrroloquinoxalines with substituted arylpiperazino or aryltetrahydropyrido chain at position 3 of the quinoxaline ring (2-(4-phenylpiperazin-1-ylmethyl)-4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3a), 2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3b), 2-[4-(3-trifluoromethylphenyl)piperazin-1-ylmethyl]-4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3c), 2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3d), 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3e), and 2-(4-phenyl1,2,3,6-tetrahydropyridin-1-ylmethyl)-4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3f)). A preliminary pharmacological study of these products was conducted using climbing behaviour induced by apomorphine (2.5 mg kg(-1), s.c.) in mice. The derivatives were administered intraperitoneally 30 min before apomorphine. Haloperidol, chlorpromazine and clozapine were used as references. Among this series, 3b, 3c and 3f revealed a central dopamine antagonist activity. The most active derivative was 3b, which exhibited a profile relatively close to clozapine.     

Identification and characterization of potential impurities of quetiapine fumarate

Seven potential impurities, including by-products, starting materials and intermediates were identified in pharmaceutical substance quetiapine fumarate and characterized by spectroscopic methods (MS, IR, NMR). Based on these methods the structures of the impurities were assigned or confirmed as: impurity I: 2-(phenylthio)aniline; impurity II: phenyl N-[2-(phenylthio)phenyl]carbamate; impurity III: N,N'-bis[2-(phenylthio) phenyl]urea; impurity IV: N-[2-(phenylthio)phenyl]-1-piperazinecarboxamide hydrochloride; impurity V: N,N'-bis[(2-phenylthio)phenyl]-1,4-piperazinedicarboxamide; impurity VI: 11-(1-piperazinyl) dibenzo[b,f][1,4]thiazepine fumarate; impurity VII: 1,4-bis(dibenzo[b,f][1,4] thiazepin-11-yl)piperazine. Structural elucidation of compounds, proposed MS fragmentation pathway and possible ways of formation of the impurities are also discussed.     

Design, synthesis, and binding affinities of potential positron emission tomography (PET) ligands for visualization of brain dopamine D3 receptors

We here report the synthesis of compounds structurally related to the high-affinity dopamine D(3) receptor ligand N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-methoxy-2-benzofurancarboxamide (1). All compounds were specifically designed as potential PET radioligands for brain D(3) receptors visualization, having lipophilicity within a range for high brain uptake and weak nonspecific binding (2 < ClogP < 3.5) and bearing a methoxy substituent for easy access to labeling with the positron emitter isotope (11)C. N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-4-(4-morpholinyl)benzamide (22), N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-4-(1H-imidazol-1-yl)benzamide (23), and N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-5-(2-furanyl)-1H-pyrazole-3-carboxamide (24) displayed good D(3) receptor affinities (K(i) values 38.0, 22.6, and 21.3 nM, respectively) and were selective over D(2) receptor. Moreover, compounds 22-24 were able to permeate the Caco-2 cell monolayer, differently from compound 1. Although the goal to identify potential PET radioligands with subnanomolar affinities for D(3) receptor was not achieved, the proposed strategy could be a starting point for future developments.     

11C-labeling of n-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]arylcarboxamide derivatives and evaluation as potential radioligands for PET imaging of dopamine D3 receptors

The selective dopamine D(3) receptor ligands N-4-[4-[(2,3-dichlorophenyl)piperazin-1-yl]butyl]1-methoxy-2-naphthalencarboxamide (1) and N-4-[4-[(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-methoxy-2-benzofurancarboxamide (2) were labeled with (11)C (t(1/2) = 20.4 min) as potential radioligands for the noninvasive assessment of the dopamine D(3) neurotransmission system in vivo with positron emission tomography (PET). The radiosynthesis consisted in an O-methylation of the des-methyl precursors N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-1-hydroxy-2-naphthalenecarboxamide (3) and N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-hydroxy-2-benzofurancarboxamide (4) with [(11)C]methyl iodide using tBuOK/HMPA and KOH/DMSO, respectively. The radiotracers [(11)C]1 and [(11)C]2 were obtained in 35 min with over 99% radiochemical purity, 74 +/- 37 GBq/mumol of specific radioactivity, 13% and 26% radiochemical yield (EOB, decay-corrected). Distribution studies in rats demonstrated that the new tracers [(11)C]1 and [(11)C]2 cross the blood-brain barrier and localize in the brain. However, the kinetics of cerebral uptake did not reflect the regional expression of the D(3) receptors. Despite their in vitro pharmacological profile, [(11)C]1 and [(11)C]2 do not display an in vivo behavior suitable to image D(3) receptor expression using PET.     

NNC 19-1228 and NNC 22-0031, novel neuroleptics with a “mesolimbic-selective” behavioral profile

NNC 19-1228 [1-(3(6-benzothiazolylcarbamoyloxy)propyl)-4-(6-flouro-1,2-benzisoxazol-3-yl)piperidine] and NNC 22-0031 [4-(6-flouro-1,2-benzisoxazol-3-yl)-1-(3-(3,4-methylenedioxyphenylcarbamoyloxy)propyl)piperidine] are newly developed compounds with an in vitro pharmacologic profile similar to that of clozapine, i.e., mixed dopamine (DA), 5-hydroxytryptamine (5-HT)₂ and α₁-adrenergic antagonist action. In pharmacological experiments in mice, the compounds inhibited DA D₂ receptor binding in vivo at doses that produced only moderate antagonism of methylphenidate (MPD)-induced stereotyped gnawing. However, the compounds were markedly more potent in blocking MPD-induced motility, a model which showed a high degree of sensitivity to α₁-adrenergic antagonism, but not 5-HT₂ antagonism. In rats, the NNC-compounds blocked conditioned avoidance responding and attenuated the discriminative stimulus effects of amphetamine, but failed to induce catalepsy. These results are discussed in terms of adrenergic, serotonergic and dopaminergic interactions which suggest that the NNC compounds may act as DA antagonists with mesolimbic selectivity, and thus may have efficacy as antipsychotics without coincident extrapyramidal side effects. Received: 16 May 1996/ Final version: 14 August 1996     

Neuroleptic piperazinyl-dibenzo-azepines. Chemistry and structure-activity relationships.

The chemistry and the molecular and physicochemical properties of the 11-piperazinyl derivatives of dibenz[b,f][1,4]-oxazepines and -thiazepines and of dibenzo[b,e][1,4]diazepines as well as those of the 6-piperazinyl-morphanthridines are reviewed. The physicochemical parameters sigma, pK, eta, RM and surface pressure are considered in relation to each other and in relation to two pharmacological effects, namely apomorphine antagonism and cataleptic activities. The influence of substituents, bridging moiety and basic side chain on structure-activity are discussed. Finally, the dibenzodiazepine derivative clozapine, which differs markedly from the classical neuroleptics in its biochemical, pharmacological and clinical properties and represents a new type of antipsychotic agent, is discussed.     

Effects of 5-HT1A agonists and 5-HT2 antagonists on haloperidol-induced dyskinesias in squirrel monkeys: no evidence for reciprocal 5-HT-dopamine interaction

Dyskinetic movements and dystonic postures may be induced by neuroleptics in monkeys that have undergone previous neuroleptic treatment, and these motor abnormalities constitute a primate model of drug-induced extrapyramidal symptomatology. In view of previous suggestions that brain serotonergic systems may tonically inhibit dopamine neurons, the effects of several new and selective 5-HT₂ receptor antagonists and 5-HT_1A receptor agonists were investigated in this model. Setoperone, a dopamine D2 receptor antagonist with extremely potent 5-HT₂ antagonism, caused dyskinetic movements. Although ritanserin is a potent 5-HT₂ antagonist with very weak dopamine antagonist properties, this drug did not antagonize dyskinesias but induced them when administered at a high dose (30 mg/kg). Buspirone induced dyskinesias and blocked apomorphine-induced climbing, supporting prior reports that it has dopamine antagonist effects. Gepirone, a 5-HT_1A agonist with less marked dopamine antagonist properties, induced dyskinesias in only one of six monkeys at 30 mg/kg and did not block haloperidol-induced dyskinesias. 8-OH-DPAT partly attenuated haloperidol-induced dyskinesias, an effect possibly attributable to its weak dopamine agonist properties. Tonic inhibition of brain extrapyramidal dopamine systems by serotonin systems does not appear to characterize neuroleptic related dyskinesias in squirrel monkeys.     

New 3-[4-(3-substituted phenyl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propanol derivatives with dual action at 5-HT1A serotonin receptors and serotonin transporter as a new class of antidepressants

In this paper a series of new 3-[4-(3-substituted phenyl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propanol derivatives is presented as a new class of antidepressant drugs with dual activity at 5-HT1A serotonin receptors and serotonin transporter. The 5-HT1A receptor and 5-HT transporter binding affinities of hydroxylic compounds 4 a-e have been determined. The new compounds present nanomolar affinity for both activities, and 1-(benzo[b]thiophen-3-yl)-3-[4-(3-methoxyphenyl)piperazin-1-yl]propan-1-ol (4d) shows values (nM) of Ki = 86 for 5-HT1A receptors and Ki = 76 for the serotonin transporter, respectively.     

Characterization of aripiprazole partial agonist activity at human dopamine D3 receptors

Aripiprazole is the first dopamine D2/D3 receptor partial agonist approved for use in the treatment of psychiatric disorders, including schizophrenia, bipolar disorder, and unipolar depression in the US. To explore the functional activity of aripiprazole at dopamine D3 receptors, we established Chinese hamster ovary (CHO) cell lines stably expressing high and low densities of Ser-9 and Gly-9 variants of human dopamine D3 receptors and compared aripiprazole's dopamine D3 pharmacological properties with other marketed and non-approved dopamine D3 receptor modulating agents on inhibition of forskolin-stimulated cAMP accumulation. Maximal cell responses for dopamine were dependent on receptor expression levels, and all cells had similar potency for dopamine responses. Aripiprazole, terguride, bifeprunox, OPC-4392 (7-(3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy)-2(1H)-quinolinone), (-)-3-PPP ((-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine), SDZ 208-912 (N-[(8 alpha)-2-chloro-6-methylergolin-8-yl]-2,2-dimethylpropanamide), BP897 (N-[4-[4-(2-Methoxyphenyl)-1-piperazinyl]butyl]naphthalene-2-carboxamide) and GR103691 (4'-Acetyl-N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]biphenyl-4-carboxamide) behaved as partial agonists. Aripiprazole's intrinsic activity was similar to that of BP897 and GR103691, lower than that of terguride, bifeprunox, OPC-4392, and (-)-3-PPP, and higher than that of SDZ 208-912. The Gly-9 variant did not differ from the Ser-9 variant with respect to those agonist potencies and intrinsic activities. These compounds blocked the action of dopamine with a maximum effect equal to that of each compound alone. ACR16 (4-(3-Methanesulfonyl-phenyl)-1-propyl-piperidine), quetiapine, clozapine, olanzapine, ziprasidone, risperidone, and haloperidol acted as antagonists. Aripiprazole's unique activity at dopamine D3 receptors may translate into clinically relevant outcomes in patients with a variety of neuropsychiatric disorders.     

Structure-affinity relationship study on N-[4-(4-arylpiperazin-1-yl)butyl]arylcarboxamides as potent and selective dopamine D(3) receptor ligands

The benzamide PB12 (N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide) (1), already reported as potent and selective dopamine D(4) receptor ligand, has been modified searching for structural features that could lead to D(3) receptor affinity. Changes in the aromatic ring linked to N-1 piperazine ring led to the identification of 2-methoxyphenyl and 2,3-dichlorophenyl derivatives (compounds 6 and 13) displaying moderate D(3) affinity (K(i) = 145 and 31 nM, respectively). Intermediate alkyl chain elongation in compounds 1, 6, and 13 improved binding affinity for the D(3) receptor and decreased the D(4) affinity (compounds 18-26). Among these latter compounds, the N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-3-methoxybenzamide (19) was further modified with the replacement or of the 2,3-dichlorophenyl moiety (compounds 27-30) or of the 3-methoxyphenyl ring (compounds 31-41). In this way, we identified several high-affinity D(3) ligands (0.13 nM < K(i)'s < 4.97 nM) endowed with high selectivity over D(2), D(4), 5-HT(1A), and alpha(1) receptors. In addition, N-[4-[4-(2,3-dimethylphenyl)piperazin-1-yl]butyl]-3-methoxybenzamide (27) and N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-methoxy-2-benzofurancarboxamide (41) appear to be valuable candidates for positron emission tomography (PET) because of their affinity values, lipophilicity properties, and liability of (11)C labeling in the O-methyl position.     

The combination of nicotine with the D2 antagonist raclopride or the weak D4 antagonist L-745,870 generates a clozapine-like facilitation of NMDA receptor-mediated neurotransmission in pyramidal cells of the rat medial prefrontal cortex

Clozapine and other atypical, but not typical, antipsychotic drugs (APDs), facilitate both dopaminergic and N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic transmission in the medial prefrontal cortex (mPFC), which is thought to improve cognition. Switching schizophrenic patients from typical APDs to clozapine may reduce their cigarette smoking. Here, we tested whether nicotine, which facilitates dopamine release, also facilitates NMDA receptor-mediated neurotransmission in the mPFC, when given alone or in combination with a D(2,3) antagonist, raclopride, or a D4 antagonist, 3-(4-[4-chlorophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2,3b]pyridine (L-745,870), using intracellular recording in pyramidal cells of the rat mPFC. Neither nicotine nor raclopride or L-745,870 alone altered NMDA-induced currents in these cells. However, combining nicotine with raclopride or L-745,870 facilitated these currents. Similarly to clozapine the combination of nicotine with raclopride or L-745,870 also markedly potentiated evoked excitatory post-synaptic potentials in the mPFC. Our results support the idea that intense smoking in schizophrenia may represent a form of self-medication with nicotine.     

Hypochlorous acid, a major oxidant produced by activated neutrophils, has low effect on two pyridobenzazepine derivatives, JL 3 and JL 13

JL 13 (5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b]- [1,5]benzoxazepine fumarate) and JL 3 (10-(4-methylpiperazin-1- yl)pyrido[4,3-b][1,4]benzothiazepine), two pyridobenzazepine derivatives structurally related to clozapine, were selected for further development. Due to their structural similarity to clozapine, they are haunted by the spectre of clozapine-induced agranulocytosis. In a previous study, JL 13 was shown to be less sensitive to oxidation than clozapine. In the present paper, using an in vitro procedure, we report the effect of hypochlorous acid (HOCl), a major in vivo oxidant, on both drugs. It appears that the oxidations of JL 3 and JL 13, unlike clozapine, are very slow and little secondary product is formed. Moreover, in contrast to clozapine, the products that were formed are not reactive and thus do not react with glutathione or N-acetylcysteine. Thus, if, as postulated for clozapine, drug-induced agranulocytosis is due to a reactive metabolite formed by neutrophils or their precursors, JL 3 and JL 13 would not be expected to cause the same adverse reaction.