Neurokinin B (NKB)-neurokinin-3 receptor (NK3R) signaling plays an important role in controlling mammalian reproduction via regulation of the hypothalamo-pituitary-gonadal (HPG) axis. NKB positively regulates the reproductive hormone cascade via activation of the gonadotropin-releasing hormone (GnRH) neuron in the hypothalamus, leading to the pulsatile secretion of luteinizing hormone (LH) from the pituitary gland. NK3R-selective antagonists could suppress the reproductive functions of mammals. However, the NK3 modulators and the bioactive metabolites excreted from treated humans or animals may cause environmental and health risks including reproductive disturbances of non-target species via water pollution and/or soil contamination. To minimize the possibility of these adverse effects on non-target species, the bioactive ingredients need be converted into the inactive substances by spontaneous degradation in the environment soon after excretion. We investigated the structure–activity relationship study a quinolone-based NK3R antagonist for development of novel antagonists with reduced environmental toxicity.<br/>Talnetant derivatives with hydroxy- or mercapto-group modifications exhibited comparable NK3R binding inhibition to that of the parent compound talnetant. Air-oxidation of 3-mercaptoquinoline derivative afforded the disulfide or isothiazolone form with no binding affinity to NK3R. This novel NK3R antagonist would be applicable to the treatment of sex-hormone disorders with decreased environmental impact.

Development of novel NK3 receptor antagonists with reduced environmental impact

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.