As part of our program aimed at the development of potent excitatory amino acid antagonists, we synthesized and evaluated a series of substituted 1,2,4-triazolo[4,3-a]quinoxalin-4(5H)-ones, 4, tetrazolo[1,5-a]quinoxalin-4(5H)-ones, 5, and pyrazolo[1,5-c]quinazolin-5(6H)-ones, 6, and an imidazo[1,2-a]quinoxalin-4(5H)-one, 7. In general, the same heterocycles which demonstrated the best affinity for the AMPA receptor also demonstrated the best affinity for the glycine site on the NMDA receptor complex. 1-Propyl-7,8-dichloro-1,2,4-triazolo[4,3-a]quinoxalin-4(5H)-one, 4d, was found to bind with the greatest affinity to the AMPA receptor with an IC50 of 0.83 microM and antagonized 40 microM AMPA-induced depolarization in the cortical slice preparation with an IC50 of 44 microM. 7,8-Dichloro-1,2,4-triazolo[4,3-a]quinoxalin-4(5H)-one, 4a, and 7,8-dichloroimidazo[1,2-a]quinoxalin-4(5H)-one, 7, possessed the best affinity for the glycine site with IC50 values of 0.63 and 1.26 microM, respectively. It is noteworthy that the SAR for the heterocyclic compounds did not directly parallel that of known quinoxalinediones (e.g. DNQX, 2, and DCQX, 15) at the AMPA receptor nor that of the kynurenic acids at the glycine site on the NMDA receptor complex.

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Androgens, in particular dihydrotestosterone (DHT), play a key role in differentiation, growth, and maintenance of the mammalian prostate. Production of DHT from testosterone is catalyzed by two distinct membrane-bound steroid 5a-reductase [5a-reductase; 3-oxo-5a-steroid A4-dehydrogenase; 3-oxo-5a-steroid:(acceptor) AW-oxidoreductase, EC 1.3.99.5] isozymes designated types 1 and 2. Benign prostatic hyperplasia (BPH), a disease that occurs almost universally in males, is characterized by obstructive and irritative urinary voiding symptoms and has been associated with an overproduction of DHT. Recently, steroidal inhibitors of 5a-reductase type 2 have been used successfully for treatment of BPH. Described here is a nonsteroidal inhibitor of 5a-reductase type 1, LY191704 {8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octaahydro-benzo[f]quinolin-3(2H)-one}. This compound was identified based on its capacity to inhibit 5a-reductase activity in a human genital skin fibroblast cell line (Hs68). Surprisingly, LY191704 is inactive when tested in freshly isolated prostate cells obtained from subjects with BPH, whereas previously described 4-azasteroids are active. LY191704 is, however, a potent inhibitor of the 5a-reductase activity of BPH cells that have been maintained in culture. Analysis of human and rat 5a-reductases expressed from transfected cDNAs in simian COS cells indicates that LY191704 is a specific noncompetitive inhibitor of the human 5a-reductase type 1. Taken together, the results suggest that prostate cells have the capacity to express both 5a-reductase isozymes and that LY191704 may be useful in treatment of human endocrine disorders associated with overproduction of DHT by 5a-reductase type 1.Prostatic hyperplasia is an age-related nonmalignant enlargement of the prostate that can result in development of obstructive and irritative urinary voiding symptoms (1, 2). For >100 years, prostatectomy has been used to treat benign prostatic hyperplasia (BPH) and is now the most common surgery performed in men >65 years old (3). Although prostatic surgery has been greatly refined, it still remains a significant cause of morbidity in elderly men (4). Recent attempts have, therefore, sought to develop pharmacological approaches for the treatment of BPH with the principal focus being on the development of agents that affect the underlying mechanisms leading to prostatic hyperplasia.Male sexual tissues show a profound dependence on the continuous presence of androgens for normal growth and function (5-8). Whereas testosterone is produced by the testes, dihydrotestosterone (DHT) is produced from testosterone in tissues by an NADPH-dependent reaction catalyzed by the membrane-bound enzyme Sa-reductase [3-oxo-The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. 5a-steroid A4-dehydrogenase; 3-oxo-5a-steroid:(acceptor) A4-oxidoreductase, EC 1.3.99.5] (9). Testosterone...