BW-1003C87

Drugs based on 5-phenyl-2,4 diamino pyrimidine and 6-phenyl-1,2,4 triazine derivatives are well known for their effects on the central nervous system.The study presented here provides detailed crystal structures of 2 pyrimidine derivatives which have neuroprotective properties in models of both gray and white matter ischemia.Recently published studies suggest that the compounds lamotrigine (a triazine derivative), and the 2 pyrimidines BW1003C87 (I) and sipatrigine (II) mediate their primary in vivo mode of action by inhibiting voltage-gated Na⁺ channels.The x-ray crystal structures will contribute valuable data for applications involving binding and modeling studies of the biol. actions of these drugs.Graphical Abstract x-ray crystallog. structures of neuroprotective pyrimidine derivatives: (I) the mesylate salt of BW1003C87 and (II) sipatrigine base Rex A. Palmer*, Brian S. Potter, Michael J. Leach and Babur Z. Chowdhry Surface representations, [20] are a useful tool with respect to considerations employed for the purposes of drug design.Shown here are the neuroprotective drug mols. (a) BW1003C87 and (b) Sipatrigine Base (BW619C89) derived from their solid state structures reported in this paper.The mols. are viewed edge on to ring B with the 2 adjacent Cl atoms uppermost on the left.

We hypothesized that blockade of synthesis or release of several categories of neurotransmitters would ameliorate opioid neurotoxicity. Rats were randomly assigned to one of six groups in two sequential protocols: vesamicol (VES, n = 10), alpha-fluoromethylhistidine (FMH, n = 10), reserpine (RES, n = 10), BW1003C87 (BW, n = 7), lamotrigine (LAM, n = 10), or one of two control groups (CON, n = 19). Physiologically controlled rats received fentanyl (fen) i.v., loading dose 800 micrograms kg-1 followed by maintenance dose 32 micrograms kg-1 min-1 for 2 h. Drug dosing: CON, isovolemic (between rats) 0.9% saline i.v.; BW, 20 mg kg-1 i.v. 15 min pre-fen; LAM, 16 mg kg-1 i.v. 30 min pre-fen; VES, 2.5 mg kg-1 i.p. 60 min and 30 min pre-fen then infused 3.75 mg kg-1 during fen; FMH, 20 mg kg-1 i.p. 2 h pre-fen; RES, 0.75 mg kg-1 i.p. 18 h pre-fen. Seven days later all rats underwent cerebral perfusion fixation, followed by histologic grading (0-5, 0 = normal). Pathological data was analyzed by Wilcoxen's Signed rank test (two-tailed) for pathologic scores summated across all brain areas (overall severity score) and for scores of areas previously associated with opioid neurotoxicity. Compared to CON, overall severity was decreased by RES (p = 0.05) with an effect suggested by VES (p = 0.10). Compared to CON, lesions were decreased: (a) in the amygdala with VES (p = 0.03) and RES (p = 0.05) with a trend suggested by BW (p = 0.06); (b) in the subiculum by VES (p = 0.02) and RES (p = 0.008) with a trend suggested by FMH (p = 0.06); and (c) in the entorhinal cortex by VES (p = 0.004) and RES (p = 0.008) with a trend suggested by FMH (p = 0.07). The data indicate that brain acetylcholine and catecholamines contribute to opioid neurotoxicity, and suggest a possible role of glutamate and histamine in opioid neurotoxicity.