TY - JOUR

T1 - Activity of novel 4-PIOL analogues at human α1β2γ2S GABAA receptors - Correlation with hydrophobicity

AU - Mortensen, Martin

AU - Frolund, Bente

AU - Jorgensen, Anne T.

AU - Liljefors, Tommy

AU - Krogsgaard-Larsen, Povl

AU - Ebert, Bjarke

N1 - Funding Information: We thank Merck Sharp & Dohme for kindly providing us with the cloned GABA A subunits. This work was supported by the Carlsberg foundation and the NeuroScience PharmaBiotec Centre in Denmark.

PY - 2002/9/13

Y1 - 2002/9/13

N2 - A series of novel 5-(4-piperidyl)-3-isoxazolol (4-PIOL) analogues where the 4-position of the 3-isoxazolol ring was substituted with groups of different size, flexibility, and lipophilicity have been characterised. Their activity as agonists and/or antagonists on human α1β2γ2S GABAA receptors expressed in Xenopus oocytes was studied using two-electrode voltage clamp electrophysiology. Methyl- and ethyl-substituted 4-PIOL analogues were characterised as partial agonists since weak agonist responses could be potentiated with lorazepam and inhibited by the competitive antagonist 2-(3-carboxypropyl)-3-amino-6-methoxyphenyl-pyradizinum bromide (SR95531). All larger substituents in the 4-position of the 3-isoxazolol ring of 4-PIOL converted the compounds into pure competitive antagonists. Additionally, for GABA, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), piperidine-4-sulphonic acid (P4S), and 5-(4-piperidyl)-3-isothiazolol (thio-4-PIOL), a negative linear correlation was found between the agonist efficacy of the compound and the ability of lorazepam to potentiate EC95 responses. Furthermore, a positive linear correlation between the lipophilicity of the substituents in the 4-position of the 3-isoxazolol ring of 4-PIOL and the antagonist affinity was found. These data suggest that the GABAA receptor contains a hydrophobic binding pocket at the GABA recognition site and that the binding of the 4-PIOL analogues is largely determined by the transfer from the aqueous phase to the hydrophobic pocket.

AB - A series of novel 5-(4-piperidyl)-3-isoxazolol (4-PIOL) analogues where the 4-position of the 3-isoxazolol ring was substituted with groups of different size, flexibility, and lipophilicity have been characterised. Their activity as agonists and/or antagonists on human α1β2γ2S GABAA receptors expressed in Xenopus oocytes was studied using two-electrode voltage clamp electrophysiology. Methyl- and ethyl-substituted 4-PIOL analogues were characterised as partial agonists since weak agonist responses could be potentiated with lorazepam and inhibited by the competitive antagonist 2-(3-carboxypropyl)-3-amino-6-methoxyphenyl-pyradizinum bromide (SR95531). All larger substituents in the 4-position of the 3-isoxazolol ring of 4-PIOL converted the compounds into pure competitive antagonists. Additionally, for GABA, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), piperidine-4-sulphonic acid (P4S), and 5-(4-piperidyl)-3-isothiazolol (thio-4-PIOL), a negative linear correlation was found between the agonist efficacy of the compound and the ability of lorazepam to potentiate EC95 responses. Furthermore, a positive linear correlation between the lipophilicity of the substituents in the 4-position of the 3-isoxazolol ring of 4-PIOL and the antagonist affinity was found. These data suggest that the GABAA receptor contains a hydrophobic binding pocket at the GABA recognition site and that the binding of the 4-PIOL analogues is largely determined by the transfer from the aqueous phase to the hydrophobic pocket.

KW - 4-PIOL (5-(4-piperidyl)-3-isoxazolol)

KW - GABA receptor

KW - Lipophilicity

KW - Partial agonist

KW - Structure-activity

KW - Xenopus oocyte

UR - http://www.scopus.com/inward/record.url?scp=0037072578&partnerID=8YFLogxK

U2 - 10.1016/S0014-2999(02)02271-9

DO - 10.1016/S0014-2999(02)02271-9

M3 - Journal article

C2 - 12231381

AN - SCOPUS:0037072578

VL - 451

SP - 125

EP - 132

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

IS - 2

ER -