Inhibition of class IIa histone deacetylase (HDAC) enzymes have been suggested as a therapeutic strategy for a number of diseases, including Huntington's disease. Catalytic-site small molecule inhibitors of the class IIa HDAC4, -5, -7, and -9 were developed. These trisubstituted diarylcyclopropanehydroxamic acids were designed to exploit a lower pocket that is characteristic for the class IIa HDACs, not present in other HDAC classes. Selected inhibitors were cocrystallized with the catalytic domain of human HDAC4. We describe the first HDAC4 catalytic domain crystal structure in a "closed-loop" form, which in our view represents the biologically relevant conformation. We have demonstrated that these molecules can differentiate class IIa HDACs from class I and class IIb subtypes. They exhibited pharmacokinetic properties that should enable the assessment of their therapeutic benefit in both peripheral and CNS disorders. These selective inhibitors provide a means for evaluating potential efficacy in preclinical models in vivo.
A series of substituted 8-styryl derivatives of 1,3,7-alkylxanthines was synthesized as potential A2-selective adenosine receptor antagonists, and the potency at rat brain A1- and A2-receptors was studied in radioligand binding experiments. At the xanthine 7-position, only small hydrophobic substituents were tolerated in receptor binding. 7-Methyl analogues were roughly 1 order of magnitude more selective for A2 versus A1 receptors than the corresponding 7-H analogues. 1,3-Dimethylxanthine derivatives tended to be more selective for A2-receptors than the corresponding 1,3-diallyl, diethyl, or dipropyl derivatives. Substitutions of the phenyl ring at the 3-(monosubstituted) and 3,5-(disubstituted) positions were favored. 1,3, 7-Trimethyl-8-(3-chlorostyryl)xanthine was a moderately potent (Ki vs [3H]CGS 21680 was 54 nM) and highly A2-selective (520-fold) adenosine antagonist. 1,3,7-Trimethyl-8-[(3-carboxy-1-oxopropyl)amino] styryl]xanthine was highly A2-selective (250-fold) and of enhanced water solubility (max 19 mM). 1,3-Dipropyl-7-methyl-8-(3,5-dimethoxystyryl) xanthine was a potent (Ki = 24 nM) and very A2-selective (110-fold) adenosine antagonist.
An adenosine antagonist, 8-(3-chlorostyryl)caffeine (CSC), was shown previously to be 520-fold selective for A,,-adenosine receptors in radioligand binding assays in the rat brain. In reversing agonist effects on adenylate cyclase, CSC was 22-fold selective for Aza receptors in rat pheochromocytoma cells (Kb 60 nM) vs. A, receptors in rat adipocytes (K,, 1.3 PM). Adrmnistered 1.p. in NIH mice at a dose of 1 mg/kg, CSC shifted the curve for locomotor depression elicited by the A,,-selective agonist APEC to the right (EDS, value for APEC shifted from 20 ,&kg i.p. to 190 @kg). CSC had no effect on locomotor depression elicited by an ED,, dose of the A,-selective agonist CHA. CSC alone at a dose of 5 mg/kg stimulated locomotor activity by 22% over control values. Coadmimstration of CSC and the A,-selective antagonist CPX, both at non-stimulatory doses, increased activity by 37% (P < 0.001) over CSC alone, suggesting a behavioral synergism of A,-and AZ-antagonist effects in the CNS.
The structure-activity relationships for a variety of adenine nucleotide analogues at P 2x -and P 2Y -purinoceptors were investigated. Compounds formed by structural modifications of the ATP molecule including substitutions of the purine ring (C2, C8, N1, and N 6 -substituents, and a uridine base instead of adenine), the ribose moiety (2′ and 3′-positions), and the triphosphate group (lower phosphates, bridging oxygen substitution, and cyclization) were prepared. Pharmacological activity at P 2Y -purinoceptors was assayed in the guinea pig taenia coli, endothelial cells of the rabbit aorta, smooth muscle of the rabbit mesenteric artery, and turkey erythrocyte membranes. Activity at P 2X -purinoceptors was assayed in the rabbit saphenous artery and the guinea-pig vas deferens and urinary bladder. Some of the analogues displayed selectivity, or even specificity, for either the P 2X -or the P 2Y -purinoceptors. Certain analogues displayed selectivity or specificity within the P 2X -or P 2Y -purinoceptor superfamilies, giving hints about possible subclasses. For example, 8-(6-aminohexylamino)ATP and 2′,3′-isopropylidene-AMP were selective for endothelial Pzypurinoceptors over P 2Y -purinoceptors in the guinea pig taenia coli, rabbit aorta, and turkey erythrocytes. These compounds were both inactive at P 2X -purinoceptors. The potent agonist N 6 -methyl ATP and the somewhat less potent agonist 2′-deoxy-ATP were selective for P 2Y -purinoceptors in the guinea pig taenia coli, but were inactive at P 2X -purinoceptors and the vascular P 2Y -purinoceptors. 3′-Benzylamino-3′-deoxyATP was very potent at the P 2X -purinoceptors in the guinea pig vas deferens and bladder, but not in the rabbit saphenous artery and was inactive at P 2Y receptors. These data suggest that specific compounds can be developed that can be utilized to activate putative subtypes of the P 2X -and P 2Y -purinoceptor classes.
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