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Synthesis and biological investigations of 3?-aminotropane arylamide derivatives with atypical antipsychotic profile.

ABSTRACT: This work is a continuation of our previous research, concentrating this time on lead structure modification to increase the 5-HT_1A receptor affinity and water solubility of designed compounds. Therefore, the compounds synthesised within the present project included structural analogues of 3?-acylamine derivatives of tropane with the introduction of a methyl substituent in the benzyl ring and a 2-quinoline, 3-quinoline, or 6-quinoline moiety. A series of novel 3?-aminotropane derivatives was evaluated for their affinity for 5-HT_1A, 5-HT_2A, and D₂ receptors, which allowed for the identification of compounds 12e, 12i, and 19a as ligands with highest affinity for the tested receptors; they were then subjected to further evaluation in preliminary in vivo studies. Selected compounds 12i and 19a displayed antipsychotic properties in the d-amphetamine-induced and MK-801-induced hyperlocomotor activity test in mice. Moreover, compound 19a showed significant antidepressant-like activity in the forced swim test in mice.

SUBMITTER: Stefanowicz J

PROVIDER: S-EPMC6061170 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Synthesis and biological investigations of 3β-aminotropane arylamide derivatives with atypical antipsychotic profile.

Stefanowicz Jacek J Słowiński Tomasz T Wróbel Martyna Z MZ Ślifirski Grzegorz G Dawidowski Maciej M Stefanowicz Zdzisława Z Jastrzębska-Więsek Magdalena M Partyka Anna A Wesołowska Anna A Turło Jadwiga J

Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents 20180622 8

This work is a continuation of our previous research, concentrating this time on lead structure modification to increase the 5-HT<sub>1A</sub> receptor affinity and water solubility of designed compounds. Therefore, the compounds synthesised within the present project included structural analogues of 3β-acylamine derivatives of tropane with the introduction of a methyl substituent in the benzyl ring and a 2-quinoline, 3-quinoline, or 6-quinoline moiety. A series of novel 3β<b>-</b>aminotropane d ...[more]

PMID: 30100693

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Project description:The beliefs that antipsychotic drugs (APDs) are 1) effective only to treat delusions and hallucinations (positive symptoms), 2) that typical and atypical APDs differ only in ability to cause extrapyramidal side effects, and 3) that their efficacy as antipsychotics is due solely to their dopamine D2 receptor blockade are outmoded concepts that prevent clinicians from achieving optimal clinical results when prescribing an APD. Atypical APDs are often more effective than typical APDs in treating negative symptoms, cognitive impairment, and mood symptoms as well as reducing the risk for suicide and decreasing aggression. This applies not only to those diagnosed with schizophrenia or schizoaffective disorder but also to bipolar disorder, major depression, and other psychiatric diagnoses. The greater advantage of an atypical APD is not evident in all patients for every atypical APD due, in part, to individual differences in genetic and epigenetic endowment and differences in the pharmacology of the atypical APDs, their mode of action being far more complex than that of the typical APDs. A common misconception is that among the atypical APDs, only clozapine is effective for reducing psychosis in treatment-resistant schizophrenia. Aripiprazole, lurasidone, olanzapine, and risperidone also can be more effective than typical APDs for treatment-resistant schizophrenia; clozapine is uniquely indicated for reducing the risk for suicide. The ability of the atypical APDs to improve cognition and negative symptoms in some patients together with lower propensity to cause tardive dyskinesia (an underappreciated advantage) leads to better overall outcomes. These advantages of the atypical APDs in efficacy and safety are due, in part, to initiation of synaptic plasticity via direct and indirect effects of the atypical APDs on a variety of proteins, especially G proteins, and release of neurotrophins (e.g., brain-derived neurotrophic factor). The typical APDs beneficial effects on psychosis are mainly the result of D2 receptor blockade, which can be associated with serious side effects and lack of tolerability.

Dataset Information

Synthesis and biological investigations of 3?-aminotropane arylamide derivatives with atypical antipsychotic profile.

Publications

Synthesis and biological investigations of 3β-aminotropane arylamide derivatives with atypical antipsychotic profile.

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