New 5-HT1A, 5HT2A and 5HT2C receptor ligands containing a picolinic nucleus: Synthesis, in vitro and in vivo pharmacological evaluation

Kaczor

et al. 2019

Archiv der Pharmazie

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N′‐Cyanoisonicotinamidine and N′‐cyanopicolinamidine derivatives, linked to an arylpiperazine moiety, were prepared and their affinities to the 5‐HT1A, 5‐HT2A, and 5‐HT2C receptors were evaluated. Several of the newly synthesized compounds, tested by binding studies, showed nanomolar affinity at the 5‐HT1A and 5‐HT2C receptors and moderate or no affinity for other relevant receptors (D1, D2, α1, and α2). Compound 8e (Ki = 21.4 nM) was the most affine for the 5‐HT2C receptor, showing, at the same time, a high selectivity with respect to the other receptors analyzed. Compounds 4a and 4c, instead, showed an interesting mixed 5‐HT1A/5‐HT2C activity with Ki values of 21.3/11.5 and 23.2/6.48 nM, respectively. The compounds with better affinity and selectivity binding profiles toward 5‐HT2C (4a, 4c, 8b, and 8e) were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that compounds 4a, 8b, and 8e exerted antidepressant‐like effects and 4a and 8e revealed also significant anxiolytic properties. Among the developed derivatives, the most promising compound seems to be 4a, which displayed antipsychotic‐, antidepressant‐ and anxiolytic‐like properties. No side effects, like catalepsy, motor‐impairment or ethanol‐potentiating effects, were observed after the injection of the tested compounds.

Section: Introductionmentioning

confidence: 99%

Synthesis, docking studies, and pharmacological evaluation of 5HT_2C ligands containing the N′‐cyanoisonicotinamidine or N′‐cyanopicolinamidine nucleus

Magli

Kaczor

et al. 2019

Archiv der Pharmazie

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“…From this point of view, it is difficult to explain the anxiolytic activity of compound 4p , which in earlier behavioral tests exerted only agonistic activity at the presynaptic receptors and no activity in relation to the postsynaptic receptors (no activity in the lower lip retraction test (LLR) . However, many compounds which interact with other receptor types, as compound 4p does, do not produce or attenuate LLR in rats .…”

Section: Discussionmentioning

confidence: 99%

“…The compounds tested in this study, 4p and 3o , are derivatives of arylpiperazine and were selected from a large group of substances. In vitro studies indicate that the new compounds are markedly selective for 5‐HT 1A receptors, and in the case of 4p , also for 5‐HT 2C receptors, without affinity for the D 1, D 2, α 1, and α 2 receptors . On this basis, we conducted studies assessing the antidepressant‐ and anxiolytic‐like activities of the new compounds, and after receiving positive results , we set out to examine the mechanisms of action of these compounds in the EPM test .…”

Section: Discussionmentioning

confidence: 99%

“…EPM stands out from these models by the fact that it uses natural stimuli such as fear of the new open spaces, which may also be anxiogenic for humans . Of note, several drugs, for example, BUS and DZ, exhibit characteristic anxiolytic effects in this test, upholding its high usefulness .…”

Section: Discussionmentioning

confidence: 99%

“…In the behavioral studies performed up to now, it has demonstrated the characteristics of presynaptic 5‐HT 1A receptor agonists, while it did not act as agonist or antagonist of postsynaptic receptors . Instead, compound 3o shows high affinity and selectivity for 5‐HT 1A receptors ( K i = 0.046 n m ) and displays the features of a postsynaptic partial agonist and a presynaptic 5‐HT 1A receptor antagonist .…”

Section: Introductionmentioning

confidence: 98%

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Anxiolytic‐like effects of the new arylpiperazine derivatives containing isonicotinic and picolinic nuclei: behavioral and biochemical studies

Fundamemntal Clinical Pharma

Fiorino

Gibuła

et al. 2019

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Anxiety disorder is a great challenge for modern psychopharmacology. Although a variety of single drugs are used in the treatment of anxiety, it is important to search for new therapeutics with faster onset of action, fewer side effects, and higher efficacy. In this work, we studied the possible anxiolytic action mechanism of two new arylpiperazine derivatives: compounds 4p N‐(3‐(4‐(piperonyl)piperazin‐1‐yl)propyl)isonicotinamide and 3o N‐(2‐(4‐(pyrimidin‐2‐yl)piperazin‐1‐yl)ethyl)picolinamide, focusing on their effects on the GABAergic and 5‐HT systems. The elevated plus‐maze test (EPM) was used for measuring anxiety. Additionally, in order to elucidate whether the new compounds have impact on the central redox balance, we conducted biochemical studies. In doing so, the relative activity of the enzymes responsible for glutathione metabolism – glutathione peroxidase and reductase (GPx and GR) – was measured. The results of the presented studies confirmed the anxiolytic effects of the new compounds 4p (60 mg/kg) and 3o (7.5 mg/kg), and suggested in the mechanism of their action, direct 5‐HT1A receptors’ participation and indirect involvement of the GABAergic system. Furthermore, the compounds exerted significant agonistic effect with buspirone (BUS, the 5‐HT1A partial agonist, 1 mg/kg i.p.) and diazepam (DZ, the classic benzodiazepine anxiolytic, 0.25 mg/kg s.c.), while WAY 100635 (N‐{2‐[4‐(2‐methoxyphenyl)‐1‐piperazinyl] ethyl}‐N‐(2‐pyridyl) cyclohexanecarboxamide, a selective 5‐HT1A antagonist, 0.1 mg/kg s.c.), but not flumazenil (a GABAA‐BDZ receptor complex antagonist, 10 mg/kg i.p.) was able to reverse their anxiolytic effects in EPM. A concomitant decrease in GPx by the compound 4p (and to a lesser degree, by compound 3o) further seemed to confirm their anxiolytic and antioxidant activity.

Synthesis, docking studies, and pharmacological evaluation of 2‐hydroxypropyl‐4‐arylpiperazine derivatives as serotoninergic ligands

Magli

Kaczor

et al. 2021

Archiv der Pharmazie

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A new series of norbornene and exo-N-hydroxy-7-oxabicyclo[2.2.1]hept-5-ene-2,3dicarboximide derivatives was prepared, and their affinities to the 5-HT 1A , 5-HT 2A , and 5-HT 2C receptors were evaluated and compared with a previously synthesized series of derivatives characterized by the same nuclei, to identify selective ligands for the subtype receptors. Arylpiperazines represent one of the most important classes of 5-HT 1A R ligands, and the research of new derivatives has been focused on the modification of one or more portions of this pharmacophore. The combination of structural elements (heterocyclic nucleus, hydroxyalkyl chain, and 4-substituted piperazine), known to be critical for the affinity to 5-HT 1A receptors, and the proper selection of substituents resulted in compounds with high specificity and affinity toward serotoninergic receptors. The most active compounds were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that 3e, 4j, and 4n were the most active and promising derivatives for the serotonin receptor considered in this study.