Crystal Structure of R 29490, an N‐methylated Analog of a Potent Steroidic Gaba‐A Antagonist: 3α‐Hydroxy‐16‐Imino‐5β‐17‐Aza‐Androstan‐11‐One, R 5135

Abstract

The synthesis of gornma-aminobutyric acid (GABA) receptor ligands is important in finding new therapeutic agerts and in helping to understand the mode of action of GABA. Amongst others, the steroid derivative 3a-hydroxy-16-imino-5pl7-aza-androstan-1 I-one, R 5135 ( Fig. la), was described as a potent GABA antagonist with an IC50 value of 0.02 pM to displace bound [3Hl GABA fiaa its A-receptor (bicuculline sensitive) (1).In order to increase the knowledge at the molecular level of the action mode of the steroid R 5135 (C1&gN2@) at the GABA-A receptor, we have studied its structural and electronic characteristics (21, as we did for other GABA-A ligands (3 -@. In order to confirm these properties, we have now solved by X-ray diffraction the crystal structure of R 29490 (C~~H~ON~@.HCI), a less active analog (Fig. lb). We report here the results. Fig. 1 : Planar suuctures of (a) R 5135 and (b) R 29490, C~~H~O N~@ . H C I , Mr = 354.64, crystals obtained from an ethyl acetate solution, crystal dimension = 0.18 xo.31 x0.10mm,monoclinic,~1,a= 10.364(1),b =7.784(2),c= 12.064(2)A,P=97.84(1) ', V=964.10A3, Z = 2, Dx = 1.22 g.cm-3, data collected on an Enraf-Nonius CAD-4 diffractometer, Mo Ka (M.71073 A), 1 = 1.72 cm-1, F (Ooa) = 386.9 range = 1-25 ' , 2169 independent reflections (-12ShS12; -5SkS9; 011S14). final R = 0.042 for 1507 observed reflections (I 2 2.5 a(I)), max. and min. heights in final A-Fourier = 0.38 and -0.35 e.A-3, noabsorption corrections made. The structure was solved using the SHELX86 program u) and refined with the SHEW76