Synthesis and Evaluation of a Series of 2-Substituted-5-Thiopropylpiperazine (Piperidine)-1,3,4-Oxadiazoles Derivatives as Atypical Antipsychotics

Abstract

BackgroundIt is important to develop novel antipsychotics that can effectively treat schizophrenia with minor side-effects. The aim of our work is to develop novel antipsychotics that act on dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors with low affinity for the serotonin 5-HT2C and H1 receptors, which can effectively cure positive symptoms, negative symptoms and cognitive impairment without the weight gain side-effect.Methodology/Principal FindingsA series of 2-substituted-5-thiopropylpiperazine (piperidine) -1,3,4-oxadiazoles derivatives have been synthesized and the target compounds were evaluated for binding affinities to D2, 5-HT1A and 5-HT2A receptors. Preliminary results indicated that compounds 14, 16 and 22 exhibited high affinities to D2, 5-HT1A and 5-HT2A receptors among these compounds. Further binding tests showed that compound 22 had high affinity for D3 receptor, and low affinity for serotonin 5-HT2C and H1 receptors. In addition, compound 22 inhibited apomorphine-induced climbing behavior and MK-801-induced hyperactivity with no extrapyramidal symptoms liability in mice. Moreover, compound 22 exhibited acceptable pharmacokinetic properties.Conclusions/SignificanceCompound 22 showed an atypical antipsychotic activity without liability for extrapyramidal symptoms. We anticipate compound 22 to be useful for developing a novel class of drug for the treatment of schizophrenia.

Synthesis and Evaluation of a Series of Piperidine‐2,6‐dione‐piperazine (piperidine) Derivatives as Multireceptor Atypical Antipsychotics

“…It should be noted that (6‐fluorobenzo[d]isoxazol‐3‐yl)piperidine derivative 5 displayed high affinities for the D 2 and 5‐HT 2A receptors (D 2 K i = 11.9 nM; 5‐HT 2A K i = 7.5 nM). These results also indicated that compounds bearing a 6‐fluorobenzo[d]isoxazol‐3‐yl)piperidine moiety ( 5 ) showed higher affinities to two receptors than those with a (benzo[d]isothiazol‐3‐yl)piperazine fragment ( 6 ) 30. Compound 15 bearing 2‐(piperidin‐4‐yl)benzo[d]oxazole showed low affinities for the D 2 and 5‐HT 2A receptors ( K i > 10 000 nM).…”

“…In fact, some of the latest efforts in the development of novel antipsychotic drugs are aimed at obtaining compounds with binding affinities for a certain number of receptors 10, 27–30. In this paper, we describe our recent efforts to discover novel antipsychotic agents with a piperidine‐2,6‐dione system linked to the arylpiperazine (piperidine) group, which is one of the most important classes for CNS activity 31–33.…”

Synthesis and Evaluation of Novel 2,3‐Dihydrobenzo[b][1,4]dioxin‐ and Indolealkylamine Derivatives as Potential Antidepressants

“…[ 3 H]8‐OH‐DPAT (187.4 Ci/mmol, Perkin Elmer Life Sciences) was used for labeling the 5‐HT 1A receptor. The assay was carried out according to the previously published procedure . Rat cerebral cortex was homogenized in 20 volumes of ice‐cold Tris–HCl buffer (50 mM, pH 7.7) using an ULTRA TURRAX homogenizer, and was then centrifuged at 32,000 g for 10 min at 4°C.…”

Synthesis of Novel Triazolyl/Oxadiazolyl/Thiadiazolyl-Piperazine as Potential Anticonvulsant Agents

“…Heterocyclic compounds forms the backbone for the discovery of many bioactive compounds. Chemical literature survey reveals that piperazine derivatives are biologically versatile compounds which possess potent antifungal [1,2], antimicrobial [3,4], antihistamine [5], antipsychotic [6,7], anticonvulsant [8][9][10] properties.…”