Newly Synthesized Fluorinated Cinnamylpiperazines Possessing Low In Vitro MAO-B Binding

Herein, we report on the synthesis and pharmacological evaluation of ten novel fluorinated cinnamylpiperazines as potential monoamine oxidase B (MAO-B) ligands. The designed derivatives consist of either cinnamyl or 2-fluorocinnamyl moieties connected to 2-fluoropyridylpiperazines. The three-step synthesis starting from commercially available piperazine afforded the final products in overall yields between 9% and 29%. An in vitro competitive binding assay using l-[3H]Deprenyl as radioligand was developed and the MAO-B binding affinities of the synthesized derivatives were assessed. Docking studies revealed that the compounds 8–17 were stabilized in both MAO-B entrance and substrate cavities, thus resembling the binding pose of l-Deprenyl. Although our results revealed that the novel fluorinated cinnamylpiperazines 8–17 do not possess sufficient MAO-B binding affinity to be eligible as positron emission tomography (PET) agents, the herein developed binding assay and the insights gained within our docking studies will certainly pave the way for further development of MAO-B ligands

Synthesis of novel 5-HT1A arylpiperazine ligands: Binding data and computer-aided analysis of pharmacological potency

Serotonin receptors modulate numerous behavioral and neuropsychological processes. Therefore, they are the target for the action of many drugs, such as antipsychotics, antidepressants, antiemetics, migraine remedies, and many others. The 5-HT1A receptors have been involved in the pathogenesis and treatment of anxiety and depression and represent a promising target for new drugs with reduced extrapyramidal side effects. In most antidepressants, a piperazine-based structural motif can be identified as a common moiety. Here we describe the synthesis, pharmacological, and in silico characterization of a novel arylpiperazines series with excellent 5-HT1A affinity. The final compounds, 4a, 8a, and 8b, were selected according to predictions of in silico pharmacokinetics, docking analysis, and molecular dynamics in conjunction with physical properties, and metabolic stability. The accentuated molecules could serve as a lead compound for developing 5- HT1A drug-like molecules for depression treatment

Synthesis, computational and pharmacological evaluation of novel N-{4-[2-(4-aryl-piperazin-1-yl)ethyl]phenyl}-arylamides

Serotonin, or 5-hydroxytryptamine (5-HT), is a biogenic amine most noted as a neurotransmitter, an activator of the utmost subtype family of G-protein- coupled receptors (GPCR). Drugs targeting 5-HT1A and other 5-HT receptors treat central nervous system diseases such as schizophrenia and depression. Recent advances in serotonin receptor structure research gave us several crystal 5-HT1A receptor structures, most notably 5-HT1A bound to the antipsychotic drug aripiprazole (Abilify®). This discovery prompted us to evaluate a series of newly synthesized ligands for serotonergic activity since those arylpiperazine derivatives share minimal general structure with aripiprazole. The results of molecular docking analysis of unsubstituted starting substances encouraged us to propound further modifications of the tail and head parts of the parent molecules to maximize receptor binding affinity. Intrigued by the results of molecular analysis, all foreseen derivatives were synthesized. The pharmacological activity of all nine (5a and 6a are synthesized previously) compounds was assessed by the in vitro tests and in silico pharmacokinetics predictions for the most promising candidates. All tested ligands have improved affinity compering to parent compounds (10a and 11a), 8b and 9b expressed the best pharmacological profile with an improved binding affinity toward serotonin 5-HT1A receptors (Ki 12.1 and 4.8 nM, respectively)

Investigation of mixed D(2)/5-HT(1A) activity of N-heteroarylmethyl-N-phenylpiperazines, N-heteroarylethyl-N-phenylpiperazines and N-heteroarylpropyl-N-phenylpiperazines

Eight novel N-heteroarylalkyl-N-phenylpiperazines have been synthesized, chemically characterized and evaluated for in vitro binding affinity at the dopamine and serotonin receptors. Synaptosomal membranes of fresh bovine caudate nuclei (D(1) and D(2)), the membranes of COS-7 cells (D(4.4)) and those prepared from fresh bovine hippocampi (5-HT(1A)) were used as a source of the corresponding receptor subtypes. [(3)H]SCH 23390 (D(1)-selective), [(3)H]spiperone (D(2)- and D(4.4)- selective) and [(3)H]-8-OH-DPAT (5-HT(1A)-selective) served as radioligands. None of the compounds expressed the affinity for the binding at the D(1) subtype receptor. Compounds 7-9 containing a single methylene group serving as a bridge between heteroaryl and N-phenylpiperazine part of the molecule were inactive [(3)H]spiperone and [(3)H]-8-OH-DPAT competitors. Ligands 15-19 (three methylene groups connecting heteroaryl- and N-phenylpiperazine part of the molecule) acted as moderate competitors of [(3)H]spiperone binding at the D(2) receptor subtype, with the exception of 15 (a thione) which expressed a high binding affinity at the D(2) receptor subtype. Compounds 15-19 behaved as moderate displacers of 8-OH-[(3)H]DPAT. Among all eight novel ligands only compound 15 expressed a moderate binding affinity at the D(4.4) receptor subtype

The Japanese way of live happily

Eight novel N-heteroarylalkyl-N-phenylpiperazines have been synthesized, chemically characterized and evaluated for in vitro binding affinity at the dopamine and serotonin receptors. Synaptosomal membranes of fresh bovine caudate nuclei (D(1) and D(2)), the membranes of COS-7 cells (D(4.4)) and those prepared from fresh bovine hippocampi (5-HT(1A)) were used as a source of the corresponding receptor subtypes. [(3)H]SCH 23390 (D(1)-selective), [(3)H]spiperone (D(2)- and D(4.4)- selective) and [(3)H]-8-OH-DPAT (5-HT(1A)-selective) served as radioligands. None of the compounds expressed the affinity for the binding at the D(1) subtype receptor. Compounds 7-9 containing a single methylene group serving as a bridge between heteroaryl and N-phenylpiperazine part of the molecule were inactive [(3)H]spiperone and [(3)H]-8-OH-DPAT competitors. Ligands 15-19 (three methylene groups connecting heteroaryl- and N-phenylpiperazine part of the molecule) acted as moderate competitors of [(3)H]spiperone binding at the D(2) receptor subtype, with the exception of 15 (a thione) which expressed a high binding affinity at the D(2) receptor subtype. Compounds 15-19 behaved as moderate displacers of 8-OH-[(3)H]DPAT. Among all eight novel ligands only compound 15 expressed a moderate binding affinity at the D(4.4) receptor subtype

In vitro and in vivo evaluation of fluorinated indanone derivatives as potential positron emission tomography agents for the imaging of monoamine oxidase B in the brain

Monoamine oxidases (MAOs) play a key role in the metabolism of major monoamine neurotransmitters. In particular, the upregulation of MAO-B in Parkinson’s disease, Alzheimer’s disease and cancer augmented the development of selective MAO-B inhibitors for diagnostic and therapeutic purposes, such as the anti-parkinsonian MAO-B irreversible binder l-deprenyl (Selegiline®). Herein we report on the synthesis of novel fluorinated indanone derivatives for PET imaging of MAO-B in the brain. Out of our series, the derivatives 6, 8, 9 and 13 are amongst the most affine and selective ligands for MAO-B reported so far. For the derivative 6-((3-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (6) exhibiting an outstanding affinity (Ki MAO-B = 6 nM), an automated copper-mediated radiofluorination starting from the pinacol boronic ester 17 is described. An in vitro screening in different species revealed a MAO-B region-specific accumulation of [18F]6 in rats and piglets in comparison to L-[3H]deprenyl. The pre-clinical in vivo assessment of [18F]6 in mice demonstrated the potential of indanones to readily cross the blood–brain barrier. Nonetheless, parallel in vivo metabolism studies indicated the presence of blood–brain barrier metabolites, thus arguing for further structural modifications. With the matching analytical profiles of the radiometabolite analysis from the in vitro liver microsome studies and the in vivo evaluation, the structure’s elucidation of the blood–brain barrier penetrant radiometabolites is possible and will serve as basis for the development of new indanone derivatives suitable for the PET imaging of MAO-B.Supplementary material: [https://cherry.chem.bg.ac.rs/handle/123456789/4592