17beta-Nitro-5alpha-androstan-3alpha-ol and its 3beta-methyl derivative: neurosteroid analogs with potent anticonvulsant and anxiolytic activities.
Many 17-substituted androstan-3alpha-ol analogs act as positive allosteric modulators of GABA(A) receptors and exert anticonvulsant and anxiolytic-like activity actions in animal models. The endogenous neurosteroid allopregnanolone (17beta-acetyl; 1) is among the most potent of these. Here we demonstrate that 3alpha-hydroxy-17beta-nitro-5alpha-androstane (2b) and its 3beta-methyl analog (3alpha-hydroxy-3beta-methyl-17beta-nitro-5alpha-androstane; 2c) modulate GABA(A) receptors as assessed by [(35)S]t-butylbicyclo-phosphorothionate and [(3)H]flunitrazepam binding with potencies equivalent to or greater than 1. These compounds also had potencies equivalent to or greater than 1 in the pentylenetetrazol and 6Hz seizure models in the mouse. Furthermore, 2b exhibited anxiolytic-like activity in the elevated zero maze. The 3beta-hydroxy, 3alpha-desmethyl analog (2a) was devoid of activity on GABA(A) receptors in vitro but had moderate activity in the seizure models, possibly as a result of epimerization in vivo at the 3-position. This conclusion was supported by the lack of in vivo activity of the 3beta-hydroxy, 3alpha-methyl analog (2d), which is not expected to undergo epimerization. We conclude that nitro can serve as a bioisostere for acetyl at the 17beta-position of 5alpha-androstan-3alpha-ol, such that the nitro analog fully retains the bioactivity of the endogenous neurosteroid at GABA(A) receptors.
Runyon
Scott P
SP
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709, USA. srunyon@rti.org
Orr
Matthew
M
Navarro
Hernán A
HA
Kepler
John A
JA
Rogawski
Michael A
MA
Kaminski
Rafal M
RM
Cook
C Edgar
CE
D000494:Allosteric Regulation; D000732:Androstanols / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry* / Q000494:pharmacology*; D000927:Anticonvulsants / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D008297:Male; D051379:Mice; D011280:Pregnanolone / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism
D000732:Androstanols; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D008024:Ligands; D011963:Receptors, GABA-A; C000658:androstan-3-ol; D011280:Pregnanolone