Pregabalin exhibits robust activity in preclinical assays indicative of potential antiepileptic, anxiolytic, and antihyperalgesic clinical efficacy. It binds with high affinity to the alpha(2)-delta subunit of voltage-gated calcium channels and is a substrate of the system L neutral amino acid transporter. A series of pregabalin analogues were prepared and evaluated for their alpha(2)-delta binding affinity as demonstrated by their ability to inhibit binding of [(3)H]gabapentin to pig brain membranes and for their potency to inhibit the uptake of [(3)H]leucine into CHO cells, a measure of their ability to compete with the endogenous substrate at the system L transporter. Compounds were also assessed in vivo for their ability to promote anxiolytic, analgesic, and anticonvulsant actions. These studies suggest that distinct structure activity relationships exist for alpha(2)-delta binding and system L transport inhibition. However, both interactions appear to play an important role in the in vivo profile of these compounds.
2-Chloro-4-(benzoyloxy)phenoI (32). To a suspension of 107.1 g (0.5 mol) of 4-(benzoyloxy)phenol7 in 1500 mL of CHC13 was added dropwise 67.5 g (0.5 mol) of S02C12 in 100 mL of CHC13 over a 30-min period. The suspension was then stirred overnight at room temperature. A small amount of undissolved material was separated by filtration and the filtrate was concentrated in vacuo to a white solid. The material was recrystallized from EtOAc: yield 73.5 g (59.2%); mp 123-124 °C. Anal. (C13H"C103) C, H, Cl.4-[6-(2-Chloro-4-hydroxyphenoxy)hexyl]-3^-diethyl'lHpyrazole (26). A mixture of 24.9 g (0.1 mol) of 2-chloro-4-(benzoyloxy)phenol (32), 29.1 g (0.1 mol) of 4-(6-bromohexyl)-3,5-heptanedione,3 27.6 g (0.2 mol) of anhydrous K2C03, 6 g of HI, and 400 mL of CH3COCH3 was refluxed with stirring for 24 h. The insoluble material was removed by filtration. The filtrate was concentrated to ~100 mL and diluted with 500 mL of (C2-HeljO, and then the organic layer was washed with H20 and dried. Removal of the solvent gave an oil, 45.9 g, which would not solidify. To a solution of 14.2 g (0.1 mol) of the oil obtained above in 50 mL of absolute C2H6OH was added 10 mL (0.2 mol) of hydrazine hydrate. The solution was refluxed with stirring for 2 h and then the solvent was removed in vacuo. To the residual oil was added 20 mL of 6 N HC1 and the mixture was stirred until a solid formed.The material was collected and recrystallized from CH3CN: yield 12.2 g (31.79%); mp 109-111 °C. Anal. (CECINA) C, , N.
The discovery of a series of chromeno[3,4-c]pyridin-5-ones with selective affinity for the dopamine D4 receptor is described. Target compounds were tested for binding to cloned human dopamine D2, D3, and D4 receptor subtypes expressed in Chinese hamster ovary (CHO) K-1 cells. Several compounds demonstrated single digit nanomolar Ki values for binding to the D4 receptor with several hundred-fold selectivities toward the D2 and D3 receptors. A limited SAR study of this series is discussed. In a mitogenesis assay measuring [3H]thymidine uptake, the target compounds showed antagonist to weak partial agonist activity at the D4 receptor, with intrinsic activities ranging from 0 to 35%. Compound 6, 3-benzyl-8-methyl-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one, increased DOPA (L-3,4-dihydroxyphenylalanine) synthesis 84% in the hippocampus and 10% in the striatum of rat brain when dosed orally at 10 mg/kg.
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