SEARCH FOR ANTAGONISTS OF NR3C4 RECEPTOR

M.I. Brylev (1), G.V. Ramenskaya (1), D.S. Lotorev (1), E.S. Mukhacheva (1), N.B. Kuznetsova (1), L.A. Pavlova (1), А.U. Lizunov (2), N.A. Pelevin (3)
1 -Sechenov First Moscow State Medical University, Russian Federation, 119991, Moscow, Trubetskaya street, 8/2;
2 -Moscow Institute of Physics and Technology (State University), Russian Federation, 141700, Moscow region, Dolgoprudny, Institutskiy per., 9;
3 -Kursk State University, Russian Federation, 305000, Kursk, Radishcheva street, 33

Introduction. One of the main types of a hormonal therapy in the treatment of the cancer of the prostate gland is the antagonists of the NR3C4 (nuclear receptor subfamily 3, group C, member 4) receptor. It blocks binding of man’s hormones with receptors site, intercepting of the appearance of biological action of this hormones in cells of prostate gland and thus stop of tumor grows. The derivatives of amino acids are used as the potential blocker of the NR3C4 receptor. These compounds aren’t xenobiotics therefore and less toxic. The aim of the study. The searches of compounds being capable of potential blocker of the NR3C4 receptor by means of the molecular modeling. There were synthesized the most perspective samples and their antagonistic activity in vitro were educe. Methods. Was made the molecular modeling of binding compounds with the NR3C4 receptor (docking) and estimation energy of binding by means of software Aglocomb. Were forecast the ADME/Т-properties of potential antagonists of the NR3C4 receptor using software Accelrys Discovery Studio. The cytotoxicity of the researched compounds was explored in the AR-UAS-blaGripTite™ 293 cells by the methodof fluorescence microscopy. The synthesis of compounds was made liquid – phase method. The antagonistic activity of the researched compounds was explored in the AR-UAS-blaGripTite™ 293 (Invitrogen K1698) using the LiveBLAzer™-FRETB/G (Invitrogen-K1095) commercial kit. Results. The searches of compounds being capable of potential blocker of NR3C4 receptor. There was performed the molecular modeling of binding substances with NR3C4 receptor. The properties of perspective antagonists of the receptor have been calculated. Because of the small size of the active site of the receptor there calculations were made among of N-acyl derivatives of the amino acids. There were synthesized 16 samples the most perspective in terms of presumptive assessments. The affinity and cytotoxicity of the synthesized samples were evaluated in vitro. The antagonistic activity for the most affinity and low-toxic compounds was revealed on the AR-UAS-blaGripTite™ 293 cells. Conclusions.The most perspective antagonists of NR3C4 receptor are samples of 2-(1-naphthyl)-ethyl ester-1-[(3-fluorophenyl)acetyl]- L-proline, 2-(1-naphthyl)-ethyl ester-1-[(4-methylphenyl)acetyl]-L-proline and 2-(1-naphthyl)-ethyl ester-1-[(4-chlorophenyl)acetyl]- L-proline.
Keywords: 
NR3C4 receptor, molecular modeling, N-acyl amino acids, the antagonistic activity