Thienopyrimidine Derivatives Specifically Activate Testicular Steroidogenesis but Do Not Affect Thyroid Functions

Abstract

The luteinizing hormone (LH) and human chorionic gonadotropin (hCG) stimulate the testosterone (T) production in Leydig cells via specifical binding to the LH/hCG receptor extracellular domain. The LH/hCG receptor can also be activated by low-molecular-weight (LMW) agonists that bind to the allosteric site located inside the transmembrane receptor channel. Since the allosteric sites in the LH/hCG and thyroid-stimulating hormone (TSH) receptors share a similar structure, LMW agonists of the LH/hCG receptor can affect activity of the TSH receptor and the synthesis of thyroid hormones which depend on this receptor. When designing selective activators of steroidogenesis, it is necessary to rule out this possibility. The aim of this study was to explore the effect of the seven previously synthesized thienopyrimidines (TPs), LMW agonists of the LH/hCG receptor, on the basal and hCG- and TSH-stimulated adenylyl cyclase (AC) activity in plasma membranes isolated from the rat testes and thyroid as well as on the basal and luliberin- and thyroliberin-stimulated levels of T and thyroid hormones following intraperitoneal (i.p.) TP administration to male rats. All seven TPs (10−4 M) increased the AC basal activity in rat testicular membranes, and in the case of combined action of TPs and hCG their stimulatory effects were additive. TPs did not affect the basal and TSH-stimulated AC activity in thyroid membranes. When administered to male rats, TPs (i.p., 25 mg/kg) increased the T level. The effect of TP03, a most active LH/hCG receptor LMW agonist, persisted under luliberin-induced activation of the gonadal axis. The nicotinamide moiety of TP21, in contrast to the structurally similar TP03, contains an additional methoxy group which alters receptor specificity of this compound. Thus, with the exception of TP21, all TPs sharing LH/hCG receptor agonistic activity, both under in vitro and in vivo conditions, do not affect the TSH receptor, indicative of their selectivity toward the gonadal axis.