Novel high-affinity and selective biaromatic 4-substituted gamma-hydroxybutyric acid (GHB) analogues as GHB ligands: design, synthesis, and binding studies.
Gamma-hydroxybutyrate (GHB) is a metabolite of gamma-aminobutyric acid (GABA) and has been proposed to function as a neurotransmitter or neuromodulator. GHB is used in the treatment of narcolepsy and is a drug of abuse. GHB binds to both GABA(B) receptors and specific high-affinity GHB sites in brain, of which the latter have not been linked unequivocally to function, but are speculated to be GHB receptors. In this study, a series of biaromatic 4-substituted GHB analogues, including 4'-phenethylphenyl, 4'-styrylphenyl, and 4'-benzyloxyphenyl GHB analogues, were synthesized and characterized pharmacologically in a [3H](E,RS)-(6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene)acetic acid ([3H]NCS-382) binding assay and in GABA(A) and GABA(B) receptor binding assays. The compounds were selective for the high-affinity GHB binding sites and several displayed Ki values below 100 nM. The affinity of the 4-[4'-(2-iodobenzyloxy)phenyl] GHB analogue 17b was shown to reside predominantly with the R-enantiomer (Ki = 22 nM), which has higher affinity than previously reported GHB ligands.
Høg
Signe
S
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
Wellendorph
Petrine
P
Nielsen
Birgitte
B
Frydenvang
Karla
K
Dahl
Ivar F
IF
Bräuner-Osborne
Hans
H
Brehm
Lotte
L
Frølund
Bente
B
Clausen
Rasmus P
RP
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002845:Chromatography / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D006801:Humans; D006885:Hydroxybutyrates / Q000138:chemical synthesis / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D011485:Protein Binding; D051381:Rats
D006885:Hydroxybutyrates; D008024:Ligands; C111420:4-hydroxybutyric acid