- Novel high-affinity and selective biaromatic 4-substituted γ-hydroxybutyric acid (GHB) analogues as GHB ligands: Design, synthesis, and binding studies
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γ-Hydroxybutyrate (GHB) is a metabolite of γ-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 GABAB 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 GABAA 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.
- H?g, Signe,Wellendorph, Petrine,Nielsen, Birgitte,Frydenvang, Karla,Dahl, Ivar F.,Br?uner-Osborne, Hans,Brehm, Lotte,Fr?lund, Bente,Clausen, Rasmus P.
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experimental part
p. 8088 - 8095
(2009/12/07)
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- A new non-steroidal anti-inflammatory analgesic: γ-oxo(1,1'-biphenyl)-4-butanoic acid (fenbufen)
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100 analogs of γ-oxo(1,1'-biphenyl)-4-butanoic acid (fenbufen) were prepared and tested using the carrageenin, polyarthritis, and UV erythema anti-inflammatory tests and the 2-phenyl-1,4-benzoquinone writhing and inflamed paw pressure analgesic tests. Only three retained the same full spectrum of activity as fenbufen: dl-4-(4-biphenyl)-4-hydroxybutyric acid, dl-4-(4-biphenylyl)-1,4-butanediol, and 4-biphenylacetic acid. Fenbufen had the same spectrum of activity as acetylsalicylic acid (ASA), phenylbutazone, and indomethacin in the five tests. In addition, dose-response derived potencies show fenbufen more potent than ASA and at least as potent as phenylbutazone in all five tests.
- Child,Osterberg,Sloboda,Tomcufcik
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p. 695 - 702
(2007/10/02)
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- Fenbufen, a new anti inflammatory analgesic: synthesis and structure activity relationships of analogs
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100 analogs of fenbufen were prepared and tested using the carrageenan, polyarthritis, and UV erythema anti inflammatory tests and the 2 phenyl 1,4 benzoquinone writhing and inflamed paw pressure analgesic tests. Only 3 retained the same full spectrum of activity as fenbufen: dl 4 (4 biphenylyl) 4 hydroxybutyric acid, dl 4 (4 biphenylyl) 1,4 butanediol, and 4 biphenylacetic acid. Fenbufen had the same spectrum of activity as aspirin, phenylbutazone, and indomethacin in the 5 tests. In addition, dose response derived potencies show fenbufen more potent than aspirin and at least as potent as phenylbutazone in all 5 tests. Two related compounds were generally similar.
- Child,Osterberg,Sloboda,Tomcufcik
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p. 466 - 476
(2007/10/05)
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