Acute administration of ␥-aminobutyric acid (GABA)-B receptor agonists decreases nicotine, cocaine, ethanol, and heroin selfadministration and also decreases food-maintained responding and suppresses locomotor activity at high doses. GABA B receptor-positive modulators may represent potentially improved therapeutic compounds because of their fewer side effects than receptor agonists. The present study investigated the effects of administration of the GABA B receptor-positive modulators 2,6-di- tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) and coadministration of the GABA B receptor-positive modulator N,NЈ-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) with the GABA B receptor agonist (3-amino-2[S]-hydroxypropyl)-methylphosphinic acid (CGP44532) on nicotineand food-maintained responding under fixed ratio (FR) 5 and progressive ratio schedules of reinforcement. Furthermore, the effects of BHF177 and CGP44532 on nicotine-induced enhancement of brain reward function were evaluated. The results indicated that administration of CGP7930 decreased nicotine selfadministration under an FR5 schedule. Administration of either GS39783 or CGP44532 selectively decreased nicotine selfadministration, whereas coadministration of these compounds had additive effects. BHF177 administration selectively decreased nicotine-but not food-maintained responding under FR5 and progressive ratio schedules. The nicotine-induced enhancement of brain reward function was blocked by BHF177 or CGP44532, although the highest doses of both compounds, particularly CGP44532, decreased brain reward function when administered alone, suggesting an additive, rather than interactive, effect. Overall, the present results indicate that GABA B receptor-positive modulators, similarly to GABA B receptor agonists, attenuated the reinforcing and reward-enhancing effects of nicotine, perhaps with higher selectivity than GABA B receptor agonists. Thus, GABA B receptor-positive modulators may be useful antismoking medications.
The optimization of GS39783 into potent, selective and safe positive allosteric modulators of GABA B receptors is presented.The receptors for the major inhibitory neurotransmitter in the central nervous system, GABA, are subdivided into ionotropic GABA A and GABA C receptors and metabotropic GABA B receptors. Whereas GABA A and GABA C receptors form chloride-permeable ion channels, GABA B receptors are G-protein coupled receptors (GPCRs). These receptors were discovered in 1980 by Norman G. Bowery 1 and act post and pre-synaptically to inhibit neuronal excitability and neurotransmitter release, respectively. A possible role of GABA B receptors in a large number of CNS disorders such as cognition deficits, anxiety, depression, epilepsy, pain and drug addiction has been discussed. 2 Some of these diseases like anxiety, pain and drug addiction could potentially be treated by activation of GABA B receptors, which can be achieved by administration of either agonists or positive allosteric modulators. Whereas benzodiazepines are well known positive allosteric modulators of GABA A receptors, the first examples of allosteric enhancers for GABA B receptors have been described only recently. 3 One of the most interesting compound found was GS39783 (Figure 1). 3b However, despite an interesting in vitro and in vivo profile, 3b,4 GS39783 was found to be genotoxic probably because of its aromatic nitro group (Figure 1) 5 5.This communication describes our efforts towards the identification of a novel, drug-like class of compounds acting as positive allosteric modulators for GABA B receptors.In order to introduce molecular diversity in position 5 of the pyrimidine ring, a 4 steps procedure depicted in Scheme 1 was optimized in order to obtain compounds with a chlorine or with a hydrogen in position 6. 4,6-dichloro-2-methylpyrimidine was first substituted by cyclopentylamine and then iodinated to lead to compound 6. This scaffold was then used in a Suzuki cross coupling 6 to give very efficiently a small focused library of substituted 4-amino-6-chloro-5-phenylpyrimidines (Cpds 7a-15a) which were then hydrogenated under standard conditions to give the desired 4-amino-5-phenylpyrimidines (Cpds 7b-15b). As a Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript means to introduce molecular diversity at the last step in position 4 of the pyrimidine ring, a versatile way of synthesis was designed (Scheme 2). Starting from the commercially available 5-bromo-2,4-dichloropyrimidine, a regioselective n...
The present results extend to BHF177 the capacity of the 2 previously tested positive allosteric modulators of the GABA(B) receptor, CGP7930 and GS39783, to specifically suppress alcohol's reinforcing and motivational properties in alcohol-preferring rats.
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