clozapine and phenylpiperazine

A series of arylpiperazinylbutyl derivatives of 4,5-dihydro-1,2,4-triazine-6(1H)-ones was designed and synthesized according to the new solid-supported methodology. In this approach, triazinone scaffold was constructed from the Fmoc-protected glycine. The library representatives showed different levels of affinity for 5-HT7 and 5-HT1A receptors; compounds 13, 14 and 18-20 were classified as dual 5-HT7 /5-HT1A receptors ligands. The structure-affinity relationship analysis revealed that the receptor affinity and selectivity of the tested compounds depended on the kind of substituent in position 3 of triazinone fragment as well as substitution pattern of the phenylpiperazine moiety.

Topics: Ligands; Piperazines; Radioligand Assay; Receptor, Serotonin, 5-HT1A; Receptors, Serotonin; Solid-Phase Synthesis Techniques; Structure-Activity Relationship; Triazines

The current study is focused on newly developed phenylpiperazine derivatives of aromatic methylhydantoin differing in mutual positions of methyl and phenyl moieties. The new compounds were synthesized using Bucherer-Bergs reaction, two-phase alkylation, Mitsunobu reaction and/or an alkylation under microwave irradiation. The compounds developed were assessed on their affinity for serotoninergic receptors 5-HT1A, 5-HT6, 5-HT7 and α1-ARs in radioligand binding assays. Selected compounds were tested on their inhibitory effect at human 5-HT3A expressed in Xenopus Oocytes as well as on their activity at α1-adrenoceptor subtypes in functional and electrophysiological bioassays, respectively. Most of investigated compounds exhibited affinities for α1-ARs, 5-HT1A, 5-HT7 (Ki ∼ 0.8-353 nM) significantly higher than those for 5-HT6 receptors. Very weak inhibitory effect at 5-HT3A accompanied with high activity at α1D-AR subtypes were observed for selected representative compounds. Among the current series, particularly 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione hydrochloride (25a) displayed the highest 5-HT7 affinity with Ki = 3 nM and selectivity with 40-3600 fold towards 5-HT1A, 5-HT6, and α1-ARs.

Topics: Dose-Response Relationship, Drug; Humans; Hydantoins; Ligands; Molecular Structure; Piperazines; Receptors, Serotonin; Structure-Activity Relationship

Using a combination of docking and molecular dynamics simulations, we predicted that p-hydroxylation by CYP1A2 would be the main metabolic pathway for the 1-[1-(4-chlorophenyl)-1H-4pyrazolylmethyl] phenylhexahydropiperazine, LASSBio-579 (3). As the result of a screening process with strains of filamentous fungi, Cunninghamella echinulata ATCC 9244 was chosen to scale up the preparation of the p-hydroxylated metabolite (4). About 30 min after i.p. administration of (3) to rats was identified as the p-hydroxylated metabolite, confirming our in silico previsions. Chemical synthesis of the metabolite was performed and allowed its pharmacological evaluation in binding assays revealing its high affinity for D2 and D4 receptors, indicating that this metabolite should participate to the antipsychotic effect of (3) in vivo. Furthermore, we report here that both (3) and its p-hydroxylated metabolite (4) have a much lower affinity than clozapine for two receptors involved in adverse reactions. Voltammetric assays were useful to understand the redox profile of (3).

Topics: Animals; Antipsychotic Agents; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Lead; Male; Models, Molecular; Molecular Dynamics Simulation; Molecular Structure; Organometallic Compounds; Piperazines; Rats; Rats, Wistar; Receptors, Dopamine D4; Structure-Activity Relationship

In an attempt to increase the affinity of our antipsychotic lead compound LASSBio-579 (1-((1-(4-chlorophenyl)-1H-pyrazol-4-yl)methyl)-4-phenylpiperazine; (2)) for the 5-HT(2A) receptor, we synthesized five new N-phenylpiperazine derivatives using a linear synthetic route and the homologation strategy. The binding profile of these compounds was evaluated for a series of dopaminergic, serotonergic and alpha-adrenergic receptors relevant for schizophrenia, using classical competition assays. Increasing the length of the spacer between the functional groups of (2) proved to be appropriated since the affinity of these compounds increased 3-10-fold for the 5-HT(2A) receptor, with no relevant change in the affinity for the D₂-like and 5-HT(1A) receptors. A GTP-shift assay also indicated that the most promising derivative (1-(4-(1-(4-chlorophenyl)-1H-pyrazol-4-yl) butyl)-4-phenylpiperazine) (LASSBio-1635) (6) has the expected efficacy at the 5-HT(2A) receptors, acting as an antagonist. Intraperitoneal administration of (6) prevented apomorphine-induced climbing behavior and ketamine-induced hyperlocomotion in mice, in a dose dependent manner. Together, these results show that (6) could be considered as a new antipsychotic lead compound.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Chemistry Techniques, Synthetic; Dose-Response Relationship, Drug; Drug Design; Locomotion; Male; Mice; Piperazines; Receptor, Serotonin, 5-HT2A; Schizophrenia

We described herein the design, synthesis, and pharmacological evaluation of N-phenylpiperazine heterocyclic derivatives as multi-target compounds potentially useful for the treatment of schizophrenia. The isosteric replacement of the heterocyclic ring at the biaryl motif generating pyrazole, 1,2,3-triazole, and 2-methylimidazole[1,2-a]pyridine derivatives resulted in 21 analogues with different substitutions at the para-biaryl and para-phenylpiperazine positions. Among the compounds prepared, 4 (LASSBio-579) and 10 (LASSBio-664) exhibited an adequate binding profile and a potential for schizophrenia positive symptoms treatment without cataleptogenic effects. Structural features of this molecular scaffold are discussed regarding binding affinity and selectivity for D(2)-like, 5-HT(1A), and 5-HT(2A) receptors.

Topics: Administration, Oral; Animals; Antipsychotic Agents; Cell Line; Humans; Ligands; Male; Mice; Piperazines; Pyrazoles; Rats; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine D2; Schizophrenia

A series of phenylpiperazine-methyl-substituted 1H-pyrrolo[2,3-c]pyridine, imidazo[1,2-c]-, pyrrolo[2,3-d]- and pyrrolo[3,2-d]pyrimidines were prepared as selective dopamine D4-ligands. The pyrrolo[2,3-d]pyrimidine derivatives 12d (K(i)=1,9 nM) and 34 d (K(i)=2,4 nM) as well as the pyrrolo[3,2-d]pyrimidine Mannich base 49f (K(i)=2,8 nM) showed high dopamine D4 receptor activity superior to the atypical antipsychotic agent clozapine.

Topics: Animals; Antipsychotic Agents; Cattle; CHO Cells; Clozapine; Cricetinae; Cricetulus; Humans; Molecular Structure; Piperazines; Protein Binding; Pyrimidines; Receptors, Dopamine; Receptors, Dopamine D4; Structure-Activity Relationship

Two new series of substituted arylpiperazines with heterocyclic 3-propoxy-benzimidazole or 3-propoxy-benzimidazole-2-thione groups were synthesized and their in vitro binding affinities for the D(2), 5-HT(1A), 5-HT(2A), and alpha(1)-adrenergic receptors determined. Among them, only two compounds with phenyl aryl-constituent (8a and 9a) showed 5-HT(2A)/D(2) pK(i) binding ratios proposed for atypical neuroleptics. As to their behavioral screening on rodents, both compounds exhibited a non-cataleptic action in rats and antagonized D-amphetamine-induced hyperlocomotion in mice, suggesting their possible atypical antipsychotic potency.

Topics: Animals; Antipsychotic Agents; CHO Cells; Cricetinae; Cricetulus; Piperazines; Rats

Generally, antipsychotic agents are dopamine receptor blocking agents that also block conditioned avoidance responding (CAR) in the rat. Recently, however, both (Q-methoxyphenyl)piperazine (OMPP, 1h) and (m-chlorophenyl)piperazine (MCPP, 1o) have been reported to block conditioned avoidance responding in the rat although neither has dopamine receptor blocking properties. The present paper examines the behavioral and biochemical profile of a number of additional substituted phenylpiperazines. None of the phenylpiperazines tested demonstrated high affinity for either dopamine D-1 or D-2 receptor sites, yet many were effective in blocking CAR. The results suggest that the phenylpiperazines may be effective antipsychotic agents without blocking dopamine receptors. Moreover, the active compounds did demonstrate activity in displacing ligand binding to serotonin receptors. Receptor binding profiles were determined for 5-HT-1A and 5-HT-1B binding sites as well as for 5-HT-2 sites. The data from this preclinical test suggest these phenylpiperazines might be effective antipsychotic agents acting via a nondopaminergic mechanism of action.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Dose-Response Relationship, Drug; Piperazines; Rats; Receptors, Dopamine; Receptors, Serotonin; Structure-Activity Relationship