Synthesis and GABA A receptor activity of 6-oxa-analogs of neurosteroids

• Published in: Steroids Vol. 65; no. 6; pp. 349 - 356
• Main Authors: Nicoletti, Daniel, Ghini, Alberto A, Furtmüller, Roman, Sieghart, Werner, Dodd, Robert H, Burton, Gerardo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2000
• Subjects: 6-Oxapregnanolone; 6-Oxasteroids; Animals; Antipsychotic Agents - chemistry; Antipsychotic Agents - pharmacology; Binding Sites; Bridged Bicyclo Compounds, Heterocyclic - metabolism; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cholestanones - chemical synthesis; Cholestanones - pharmacology; Flunitrazepam - metabolism; Flunitrazepam - pharmacology; GABA; GABA A receptor; GABA Modulators - chemistry; GABA Modulators - pharmacology; Hydrogen Bonding; Inhibitory Concentration 50; Molecular Structure; Muscimol - metabolism; Muscimol - pharmacology; Neurosteroids; Rats; Receptors, GABA-A - drug effects; Receptors, GABA-A - metabolism; Steroid; Steroids - chemistry; Structure-Activity Relationship; Steroid; GABA; 6-Oxasteroids; Neurosteroids; GABA A receptor; 6-Oxapregnanolone
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/S0039-128X(00)00088-X

The 6-oxasteroids 3α-hydroxy-6-oxa-5α-pregnan-20-one (
3) and 3α-hydroxy-6-oxa-5β-pregnan-20-one (
4) were obtained from pregnenolone acetate via the corresponding (5α or 5β) 3β,20β-diacetoxy-6-oxa-pregnane. Both steroids showed ca. 100-fold reduced potency for modulating [
3H]flunitrazepam, [
3H]muscimol or [
35S]TBPS binding to the GABA
A receptor when compared to their natural carbon analogs 3α-hydroxy-5α-pregnan-20-one (
1) and 3α-hydroxy-5β-pregnan-20-one (
2).