Activity of B-nor analogues of neurosteroids on the GABA(A) receptor in primary neuronal cultures.
A GABA(A) receptor study of several B-nor analogues of allopregnanolone and pregnanolone has been carried out. B-norallopregnanolone (i.e., 3alpha-hydroxy-7-nor-5alpha-pregnan-20-one) was found comparable to allopregnanolone when measured with labeled TBPS. Analogous results were obtained from their effect on neurons in culture: this time, both 3alpha-hydroxy-7-nor-5xi-pregnan-20-ones (5 and 6) were found to stimulate [3H]flunitrazepam binding and GABA-induced 36Cl- influx. These effects were inhibited by GABA(A) receptor antagonists. Other analogues carrying electronegative substituents (epoxides 9 and 10 and ketone 12) in the B ring were inactive. Similarly, B-normal ketones 17, and 18 and 6-azasteroids 20 and 21 were also inactive. B-Nor analogues 5 and 6 did not induce neurotoxicity at relevant concentrations. A computational analysis of active and inactive neurosteroid analogues allowed the proposal of a 3D pharmacophoric hypothesis of their interaction with the GABA(A) receptor.
Suñol
Cristina
C
Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas, CSIC-IDIBAPS, Barcelona, Spain.
García
Daniel A
DA
Bujons
Jordi
J
Kristofíková
Zdena
Z
Matyás
Libor
L
Babot
Zoila
Z
Kasal
Alexander
A
D000818:Animals; D000838:Anions; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D003198:Computer Simulation; D018757:GABA Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D019579:Neocortex / Q000166:cytology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000838:Anions; D002712:Chlorides; D018757:GABA Modulators; D011963:Receptors, GABA-A; D011280:Pregnanolone