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 aged people.
Objective: 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).
Methods: 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 androgendependent 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.
Results: 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.
Conclusion: 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.
Keywords: 2-aminonaphthalene-1, 4-dione-derivatives, neurosteroids, 3β-hydroxysteroid dehydrogenase, 3α and 3β- androstanediol, androgen-dependent glands, improvement of memory.
Graphical Abstract
[http://dx.doi.org/10.1016/j.psyneuen.2012.01.008] [PMID: 22341731]
[PMID: 8895976]
[http://dx.doi.org/10.1210/js.2016-1029] [PMID: 29264442]
[http://dx.doi.org/10.1159/000452499] [PMID: 27855417]
[http://dx.doi.org/10.1093/carcin/21.3.427] [PMID: 10688862]
[http://dx.doi.org/10.1016/j.steroids.2013.10.012] [PMID: 24189185]
[http://dx.doi.org/10.1002/ardp.201900170] [PMID: 31602720]
[http://dx.doi.org/10.1080/07391102.2017.1413423] [PMID: 29199524]
[http://dx.doi.org/10.3390/molecules19056809] [PMID: 24858268]
[http://dx.doi.org/10.1111/j.1476-5381.2010.00826.x] [PMID: 20718744]
[http://dx.doi.org/10.3892/ijo.2014.2306] [PMID: 24573652]
[http://dx.doi.org/10.1016/S0021-9258(17)42733-5] [PMID: 6746659]
[http://dx.doi.org/10.1016/S1385-299X(02)00146-0] [PMID: 12034332]
[http://dx.doi.org/10.1081/SCC-200030621]
[http://dx.doi.org/10.1007/s11172-005-0437-7]
[http://dx.doi.org/10.1080/00304949509458181]
[http://dx.doi.org/10.1016/0040-4039(96)00738-1]
[http://dx.doi.org/10.1074/jbc.M105610200] [PMID: 11514561]
[http://dx.doi.org/10.1007/s00894-008-0420-y] [PMID: 19066990]
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[http://dx.doi.org/10.1039/c3mb70181f] [PMID: 24626770]
[http://dx.doi.org/10.1093/nar/gkv315] [PMID: 25873628]
[http://dx.doi.org/10.2174/1573408015666191105144355]
[http://dx.doi.org/10.1016/0003-2697(76)90527-3] [PMID: 942051]
[http://dx.doi.org/10.1016/0960-0760(96)00050-7] [PMID: 8903421]
[http://dx.doi.org/10.1016/S0021-9258(18)93542-8] [PMID: 4384673]
[http://dx.doi.org/10.1248/cpb.52.535] [PMID: 15133203]
[http://dx.doi.org/10.1210/endo-116-1-132] [PMID: 3871084]
[http://dx.doi.org/10.1007/s00359-017-1222-4] [PMID: 29063284]
[http://dx.doi.org/10.1016/0022-4731(84)90182-1] [PMID: 6323860]
[http://dx.doi.org/10.3923/ajava.2010.202.209]
[http://dx.doi.org/10.1126/science.1853201] [PMID: 1853201]
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[http://dx.doi.org/10.1074/jbc.M313308200] [PMID: 14672942]
[http://dx.doi.org/10.1507/endocrj1954.28.499] [PMID: 6963921]
[http://dx.doi.org/10.1210/jc.84.9.3217] [PMID: 10487690]
[http://dx.doi.org/10.1016/j.molstruc.2017.08.066]
[http://dx.doi.org/10.1002/1099-0690(200111)2001:22<4313:AIDEJOC4313>3.0.CO;2-J]
[http://dx.doi.org/10.1021/np030450f] [PMID: 15217280]
[http://dx.doi.org/10.1016/j.jconrel.2017.09.001] [PMID: 28887135]