title: Novel 17beta-substituted conformationally constrained neurosteroids that modulate GABA A receptors.
abstract: The goal of this study was to develop a series of allopregnanolone analogues substituted by conformationally constrained 17beta side chains to obtain additional information about the structure-activity relationship of 5alpha-reduced steroids to modulate GABA(A) receptors. Specifically, we introduced alkynyl-substituted 17beta side chains in which the triple bond is either directly attached to the 17beta-position or to the 21-position of the steroid skeleton. Furthermore, we investigated the effects of C22 and C20 modification. The in vitro binding affinity for the GABA(A) receptor of the new analogues was measured by allosteric displacement of the specific binding of [(3)H]4'-ethynyl-4-n-propyl-bicycloorthobenzoate (EBOB) to GABA(A) receptors on synaptosomal membranes of rat cerebellum. An allosteric binding model that has been successfully applied to ionotropic glycine receptors was employed. The most active derivative is (20R)-17beta-(1-hydroxy-2,3-butadienyl)-5alpha-androstane-3-ol (20), which possesses low nanomolar potency to modulate cerebellar GABA(A) receptors and is 71 times more active than the control compound allopregnanolone. Theoretical conformational analysis was employed in an attempt to correlate the in vitro results with the active conformations of the most potent of the new analogues.
authors.affiliation: Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635 Athens, Greece.
authors.forename: Charikleia
authors.initials: C
authors.lastname: Souli
authors.forename: Nicolaos
authors.initials: N
authors.lastname: Avlonitis
authors.forename: Theodora
authors.initials: T
authors.lastname: Calogeropoulou
authors.forename: Andrew
authors.initials: A
authors.lastname: Tsotinis
authors.forename: Gábor
authors.initials: G
authors.lastname: Maksay
authors.forename: Tímea
authors.initials: T
authors.lastname: Bíró
authors.forename: Aggeliki
authors.initials: A
authors.lastname: Politi
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
authors.forename: Heribert
authors.initials: H
authors.lastname: Reis
authors.forename: Manthos
authors.initials: M
authors.lastname: Papadopoulos
mesh_terms: D000495:Allosteric Site; D000732:Androstanols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D018757:GABA Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: C503897:17-(1-hydroxy-2,3-butadienyl)androstan-3-ol; D000732:Androstanols; D018757:GABA Modulators; D021122:Protein Subunits; D011963:Receptors, GABA-A