Anxiolytic effects of <i>N</i>-(4,5-dihydro-5-oxo-1,2-dithiolo-[4,3,b]-pyrrole-6-yl)-<i>N</i>-methylformamide, a pyrroloformamide isolated from a marine <i>Streptomyces</i> sp., in adult zebrafish by the 5-HT system
Creators: name: de F. Cesário, Hozana Patrícia S.
name: Silva, Francisca Crislândia O.
name: Ferreira, Maria Kueirislene A.
name: de Menezes, Jane Eire S. A.
name: dos Santos, Hélcio S.
name: da Fonseca, Aluísio Marques
name: Nogueira, Carlos Emídio S.
name: Marinho, Marcia M.
name: Marinho, Emmanuel S.
name: Teixeira, Alexandre Magno R.
name: Silveira, Edilberto R.
name: Pessoa, Otília Deusdênia L.
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biochemistry
subject: Genetics
subject: FOS: Biological sciences
subject: Pharmacology
subject: Biological Sciences not elsewhere classified
subject: Science Policy

description: General anxiety disorders are among the most prevalent mental health problems worldwide. The emergence and development of anxiety disorders can be due to genetic (30–50%) or non-genetic (50–70%) factors. Despite medical progress, available pharmacotherapies are sometimes ineffective or can cause undesirable side effects. Thus, it becomes necessary to discover new safe and effective drugs against anxiety. This study evaluated the anxiolytic effect in adult zebrafish (<i>Danio rerio</i>) of a natural pyrroloformamide (PFD), <i>N</i>-(4,5-dihydro-5-oxo-1,2-dithiolo-[4,3,b]-pyrrole-6-yl)-<i>N</i>-methylformamide, isolated from a <i>Streptomyces</i> sp. bacterium strain recovered from the ascidian <i>Eudistoma vannamei</i>. The complete structure of PFD was determined by a detailed NMR analysis, including <sup>1</sup>H–<sup>13</sup>C and <sup>1</sup>H–<sup>15</sup>N-HBMC data. In addition, conformational and DFT computational studies also were performed. A group of fishes (<i>n</i> = 6) was treated orally with PFD (0.1, 0.5 and 1.0 mg/mL; 20 μL) and subjected to locomotor activity and light/dark tests, as well as, acute toxicity 96 h. The involvement of the GABAergic and serotonergic (5-HT) systems was investigated using flumazenil (a silent modulator of GABA receptor) and 5-HT<sub>1</sub>, 5-HT<sub>2A/2C</sub> and 5-HTR<sub>3A/3B</sub> receptors antagonists, known as pizotifen, granisetron and cyproheptadine, respectively. PFD was nontoxic, reduced locomotor activity and promoted the anxiolytic effect in zebrafish. Flumazenil did not inhibit the anxiolytic effect of the PFD via the GABAergic system. This effect was reduced by a pretreatment with pizotifen and granisetron, and was not reversed after treatment with cyproheptadine. Molecular docking and dynamics studies confirmed the interaction of PFD with the 5-HT receptor. Communicated by Ramaswamy H. Sarma Pyrroloformamide (PFD), isolated from the marine <i>Streptomyces</i> sp. associated ascidian <i>Eudistoma vannamei</i>, showed no toxicity in adult zebrafish but reduced its locomotor activity. The structural elucidation of PFD was determined by the analysis of 1D and 2D NMR and HRESIMS data. The density functional theory (DFT) study confirmed the existence of two conformers as determined by NMR spectra. The serotonergic system modulated the anxiolytic effect of PFD via the 5-HT receptor in adult zebrafish. Molecular docking and dynamics studies confirmed the interaction of PFD with the 5-HT receptor.