New nonsteroidal molecules as blockers of the steroidogenic pathway

Abstract

Background: Testosterone circulating levels decrease in aging. This fact affects the emotional response to captivating pictures. Therefore, naturally increasing androgens within neurons could be a way to improve the mood of agedpeople. This study aimed to determine the biological activity of new nonsteroidal derivatives of 2-aminonaphthalene-1,4-dione (2-amino-3-iodonaphthalene-1,4-dione and 2-(iodoamino)-3-methylnaphthalene-1,4-dione) as inhibitors of the aldo-keto reductase 1 enzymes (AKR1C1, AKR1C2). The 2-amino-3-iodonaphthalene-1,4-dione and 2-(iodoamino)-3-methylnaphthalene-1,4-dione were synthesized, and their effect in vivo and in vitro was determined. The human prostate cell membrane was used as a source of steroidogenic enzymes. The 2-amino-3-iodonaphthalene-1,4-dione and 2-(iodoamino)-3-methylnaphthalene-1,4-dione bindings to the androgen receptors were also assayed using cytosol from the rat prostate. In vivo experiments, we determined the effects of 2-amino-3-iodonaphthalene-1,4-dione, 2-(iodoamino)-3-methylnaphthalene-1,4-dione on the weight of androgen-dependent glands of castrated hamsters treated with testosterone and finasteride or 2-amino-3-iodonaphthalene-1,4-dione or 2-(iodoamino)-3-methylnaphthalene-1,4-dione was determined. 2-amino-3-iodonaphthalene-1,4-dione and 2-(iodoamino)-3-methylnaphthalene-1,4-dione inhibited AKR1C1 enzyme activity with an IC50 value of 420 nM (2-amino-3-iodonaphthalene-1,4-dione) and 1.95 µM (2-(iodoamino)-3-methylnaphthalene-1,4-dione), respectively. They also blocked AKR1C2 with an IC50 value of 300 nM (2-amino-3-iodonaphthalene-1,4-dione) and 1.52 µM (2-(iodoamino)-3-methylnaphthalene-1,4-dione). Thus 2-amino-3-iodonaphthalene-1,4-dione and 2-(iodoamino)-3-methylnaphthalene-1,4-dione prevent the formation of 3α and 3β-androstanediols. Moreover, these compounds did not bind to AR and did not reduce prostate and seminal vesicle weight. The latter is because of the accumulation of dihydrotestosterone, which is an anabolic androgen. 2-amino-3-iodonaphthalene-1,4-dione and 2-(iodoamino)-3-methylnaphthalene-1,4-dione inhibited AKR1C1 and AKR1C2 enzyme activity; consequently, dihydrotestosterone was accumulated in androgen-dependent glands. These derivatives could potentially use therapeutics via direct nasal administration in aged patients, increasing DHT in neurons.