Syntheses and optimization of new GS39783 analogues as positive allosteric modulators of GABAB receptors

Abstract

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...

Neurobiology of nicotine dependence

“…Interestingly, GABA B receptorpositive allosteric modulator compounds, such as GS39783 and the more recently synthesized BHF177, are likely to have more subtle effects than GABA B receptor agonists, due to their modulatory, rather than full agonist, properties at the receptors (Guery et al 2007). Accordingly, such compounds do not impair performance in the rotarod test when administered alone (Cryan et al 2004).…”

Discriminative Stimulus Effects of the GABAB Receptor-Positive Modulator rac-BHFF: Comparison with GABAB Receptor Agonists and Drugs of Abuse

“…Several compounds have been shown to have positive GABA B modulatory activity in vitro [e.g., 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol (CGP7930) (Urwyler et al, 2001;Adams and Lawrence, 2007), N,N9-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (Urwyler et al, 2003), (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran -2-one (rac-BHFF) (Malherbe et al, 2008), N-[(1R,2R,4S)-bicyclo [2.2.1]hept-2-yl]-2-m ethyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) (Guery et al, 2007;Maccioni et al, 2009), methyl-2-(1-adamantanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate and methyl-2-(cyclohexanecarboxamido)-4-ethyl-5-methyltiophene-3-carboxylate (Castelli et al, 2011), and 2-{1-[2-(4-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-2-piperidinyl}ethanol (Perdona et al, 2011)]. Their positive GABA B modulatory activity in vitro was evidenced by enhancing GABA, and, for all compounds except BHF177, also by enhancing the GABA B receptor agonist baclofen.…”

Effects of the GABAB Receptor-Positive Modulators CGP7930 and rac-BHFF in Baclofen- and γ-Hydroxybutyrate-Discriminating Pigeons

“…Several compounds have been shown to have positive GABA B modulatory activity in vitro [2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol (CGP7930) (Urwyler et al, 2001;Adams and Lawrence, 2007), N, (Urwyler et al, 2003), (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) (Malherbe et al, 2008), N- [(1R,2R,4S)bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) (Guery et al, 2007;Maccioni et al, 2009), methyl-2-(1-adamantanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR627), and methyl-2-(cyclohexanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR628) (Castelli et al, 2012)], evidenced by enhancing GABA, and, for all compounds except BHF177, also by enhancing the GABA B receptor agonist baclofen. In vivo results suggest positive GABA B receptor modulators to have anxiolyticand antidepressant-like properties in elevated-maze and forced-swimming tests, respectively (Cryan et al, 2004;Frankowska et al, 2007;Jacobson and Cryan, 2008).…”