title: [Activation of adenylyl cyclase in rats testes and ovaries using thienopyrimidine derivatives].
abstract: Signaling systems regulated by luteinizing hormone (LH) and human chorionic gonadotropin (hCG) and having LH receptor as a sensor component play an important role in the functioning of the reproductive tissues. The use of LH and hCG in medicine for the treatment of diseases of the reproductive system and in auxiliary reproductive technologies is limited by their high cost, the need to use parenteral administration, and side effects. In recent years there has been the development of low molecular weight agonists of LH receptor that are devoid of these disadvantages and can be administered orally. The most effective among them are thienopyrimidine derivatives, in particular compound Org 43553. The purpose of this study was to investigate the influence of newly synthesized analogs of Org 43553, 5-amino-N-(tert-butyl)-4-(3-(isonicotinamide)phenyl)-2-(methylthio)thieno[2,3-d]pyrimidine-6-carboxamide (compound 1) and 5-amino-N-(tert-butyl)-2-(methylthio)-4--(3-(thiophene-3-carboxamido)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 2), on the basal and LH-stimulated adenylyl cyclase (AC) activity in plasma membranes fractions isolated from rat testes and ovaries. Compounds 1 and 2 have been shown to stimulated the basal AC activity in membranes isolated from the testes and ovaries in a dose dependent manner, and compound 2 was more effective in comparison with compound 1. EC50 values for the effects of the compounds 1 and 2 on the AC activity were 1.05-1.12 and 0.28-0.37 μM, respectively. Stimulating effect of hCG on the AC activity retained in the presence of the thienopyrimidine derivatives, and at low, non-saturating, concentrations of the hormone the additivity of the effects ofhCG and compounds 1 and 2 on AC activity was observed. This indicates that the thienopyrimidine derivatives interact with allosteric site localized in the transmembrane channel of LH receptor, and do not overlap with the binding site of gonadotropins, located in the N-terminal ectodomain. Effect of compounds 1 and 2 was tissue specific, and was not found in tissues where no LH receptors. Our data indicate that compounds 1 and 2 may be a prototype for drugs that regulate the function of male and female reproductive systems.
authors.forename: A O
authors.initials: AO
authors.lastname: Shpakov
authors.forename: K V
authors.initials: KV
authors.lastname: Derkach
authors.forename: D V
authors.initials: DV
authors.lastname: Dar'in
authors.forename: P S
authors.initials: PS
authors.lastname: Lobanov
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000494:Allosteric Regulation; D000495:Allosteric Site; D000818:Animals; D020134:Catalytic Domain; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007986:Luteinizing Hormone / Q000235:genetics / Q000378:metabolism; D008297:Male; D009928:Organ Specificity; D010053:Ovary / Q000187:drug effects* / Q000201:enzymology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011974:Receptors, LH / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013737:Testis / Q000187:drug effects* / Q000201:enzymology
chemical_list: D006063:Chorionic Gonadotropin; D011743:Pyrimidines; D011974:Receptors, LH; C476003:thienopyrimidine; D007986:Luteinizing Hormone; D000262:Adenylyl Cyclases