N‐{[2‐(4‐Phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides with Dopamine D₂ and 5‐Hydroxytryptamine 5HT_1A Activity: Synthesis, Testing, and Molecular Modeling

Abstract

The ratio of affinities toward the dopamine D₂ and the 5-hydroxytryptamine 5-HT(1A) receptors is one of the important parameters that determine the efficiency of antipsychotic drugs. Here, we present the synthesis of ortho-, meta-, and para-N-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-arylamides and their structure-activity relationship studies on dopamine D₂ and 5-hydroxytryptamine 5-HT(1A) receptors. It was shown that the biological activity of the described ligands strongly depends on their topology as well as on the nature of the heteroaryl group in the head of the molecules. Docking simulations together with conformational analysis revealed a rational explanation for the ligands' behavior. The molecular model of receptor-ligand interactions described herein provided us with a tool for the rational design of new compounds with a favorable D₂/5-HT(1A) profile.

Neuroprotective arylpiperazine dopaminergic/serotonergic ligands suppress experimental autoimmune encephalomyelitis in rats

“…In the present study, a somewhat better efficiency of 6b , reflected in the later onset and lower maximal disease score (Table ), correlated with its higher binding affinities for D 2 ( K i 1400 and 71.6 nM for 6a and 6b , respectively) and 5‐HT 1A receptors ( K i 304.9 and 2.4 nM) (Sukalovic et al . ). Therefore, it is possible that dopamine/serotonine receptor binding in arylpiperazine‐mediated beneficial effects in neuroinflammation.…”

“…Finally, it should be noted that the arylpiperazines investigated in the present study act as D 2 and 5‐HT 1A receptor ligands (Sukalovic et al . ), displaying partial D 2 agonist activity (Tovilovic et al ., unpublished results). In the present study, a somewhat better efficiency of 6b , reflected in the later onset and lower maximal disease score (Table ), correlated with its higher binding affinities for D 2 ( K i 1400 and 71.6 nM for 6a and 6b , respectively) and 5‐HT 1A receptors ( K i 304.9 and 2.4 nM) (Sukalovic et al .…”

“…Moreover, we have recently reported that in a series of 19 novel arylpiperazine‐based dopaminergic/serotonergic ligands (Sukalovic et al . ), N‐{4‐[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐picolinamide ( 6a ) and N‐{3‐[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐picolinamide ( 6b ) were the most potent in exerting an in vitro neuroprotective activity against the free radical nitric oxide (NO) and neurotoxin 6‐hydroxydopamine (6‐OHDA) (Tovilovic et al . , ).…”

Identification of NQO1 and ferrochelatase as interaction partners for neuroprotective N‐{[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides

“…In our previous publications, we demonstrated that N ‐{[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides of the structural formula shown in Scheme provides neuroprotection in vitro and in vivo through a stabilizing mitochondria function but not through their dopaminergic and serotonergic properties . In cell‐based model of nitric oxide‐mediated neurotoxicity, their protective effect was associated with the inhibition of proapoptotic (JNK, ERK, and AMPK) and activation of antiapoptotic (Akt) signaling pathways .…”

Synthesis, Biological, and Computational Evaluation of Substituted 1‐(2‐Methoxyphenyl)‐4‐(1‐phenethylpiperidin‐4‐yl)piperazines and 1‐(2‐Methoxyphenyl)‐4‐[(1‐phenethylpiperidin‐4‐yl)methyl]piperazines as Dopaminergic Ligands

“…In our previous publication , we showed that among N ‐arylpiperazines examined, the compounds with more flexible molecules expressed higher D 2 DAR affinity than rigid ones. This paper presents a further examination of the impact of molecule rigidity and functionalization of N ‐arylpiperazines on their D 2 DAR affinity.…”