Differential interactions of lamotrigine and related drugs with transmembrane segment IVS6 of voltage-gated sodium channels.

Voltage-gated sodium channels are blocked by local anesthetic and anticonvulsant drugs. A receptor site for local anesthetics has been defined in transmembrane segment S6 in domain IV (IVS6) of the alpha subunit, but the anticonvulsant lamotrigine and related compounds have more complex structures than local anesthetics and may interact with additional amino acid residues. Apparent K(D) values for inactivated-state block of rat brain type IIA sodium channels expressed in Xenopus oocytes were 31.9 micro M, 17.3 micro M, 3.7 micro M and 10.3 micro M for lamotrigine and compounds 227c89, 4030w92 and 619c89, respectively. Compound 619c89 was the strongest frequency-dependent blocker, which correlated with higher affinity and a five-fold slower recovery from drug block compared to lamotrigine. Examination of lamotrigine block of mutant sodium channel alpha subunits, in which alanine had been substituted for each individual amino acid in IVS6, identified mutations I1760A, F1764A and Y1771A as causing the largest reductions in affinity (six-, seven- and 12-fold, respectively). The ratios of effects of these three mutations differed for compounds 227c89, 4030w92, and 619c89. The amino acid residues interacting with these pore-blocking drugs define a surface of IVS6 that is exposed to the pore and may rotate during gating.

Voltage-gated sodium channels as therapeutic targets.

Voltage-gated sodium channels (VGSCs) play a central role in the generation and propagation of action potentials in neurons and other cells. VGSC modulators have their origins in empirical pharmacology and are being used as local anaesthetics, antiarrhythmics, analgesics and antiepileptics, and for other disorders. However, the identification of a multigene family of VGSCs, along with tools to study the different subtypes in pathophysiology, is now providing a rational basis for selective intervention. Recent advances have addressed the technical challenges of expressing and assaying these complex proteins, enabling the correlation of empirical pharmacology to subtypes and the screening of individual subtypes for novel inhibitors with increased potency and selectivity.

Acute non-lymphocytic leukemia with t(16;21).

A patient with ANLL FAB subtype M1 was found to possess a t(16;21)(p11;q22) and trisomy 10. The 16;21 translocation has been reported in 12 other cases of ANLL, of various subtypes, and its relationship to the disease profile is discussed.

BW619C89, a glutamate release inhibitor, protects against focal cerebral ischemic damage.

BACKGROUND AND PURPOSE: The excitatory amino acid neurotransmitter glutamate is involved in excitotoxic brain injury and neurodegeneration after cerebral ischemia. Therefore, compounds that block the release of glutamate may be useful as cerebroprotective agents. The purpose of this study was to evaluate the cerebroprotective properties of a glutamate release inhibitor, BW619C89. METHODS: In the studies reported here, the effect of BW619C89 [4-amino-2-(4-methyl-1-piperazinyl)-5-(2,3,5-trichlorophenyl)pyrimidine] on neurotransmitter release (endogenous amino acids, gamma-aminobutyric acid, and acetylcholine) from slices of rat brain cerebral cortex in vitro has been determined. The neuroprotective efficacy of BW619C89 has been evaluated using the middle cerebral artery occlusion model of focal cerebral ischemia in the Fischer 344 rat. RESULTS: In the in vitro studies, BW619C89 inhibited veratrine- (but not potassium-) evoked release of both endogenous glutamate and aspartate from rat cerebral cortex slices with IC50 values of approximately 5 microM. BW619C89 was approximately 10-fold less potent to inhibit veratrine-evoked 3H-gamma-aminobutyric acid release (IC50 = 51 microM), fourfold less potent to inhibit 3H-acetylcholine release (IC50 = 21 microM), and at 10 microM had only weak activity at excitatory amino acid (N-methyl-D-aspartate, kainate, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) binding sites. When administered intravenously to Fischer 344 rats 5 minutes after permanent middle cerebral artery occlusion, BW619C89 produced marked reductions of both total (cortex and basal ganglia) and cortical infarct volumes. Cortical infarct size was reduced by 20% at a dose of BW619C89 of 5 mg/kg (n = 6, not significant); 43% at 10 mg/kg (n = 8, P < .01); 59% at 20 mg/kg (n = 8, P < .001); 61% at 30 mg/kg (n = 8, P < .001), and 53% at 40 mg/kg (n = 8, P < .001). BW619C89 at doses of 20 and 30 mg/kg also significantly reduced noncortical (basal ganglia) infarct volumes, demonstrating that a proportion of this tissue also appears to be salvageable. Behavioral effects observed were dose related, generally minor, and at doses of 20 mg/kg IV and above consisted of body tremor and mild ataxia lasting approximately 2 hours. CONCLUSIONS: These results suggest that glutamate release inhibitors such as BW619C89 may provide an alternative to excitatory amino acid receptor antagonists in the treatment of focal cerebral ischemia and stroke.

Inotropic activities of imidazopyridines.

A series of 2-substituted 1H-imidazo[4,5-b]pyridines and the isomeric 1H-imidazo[4,5-c]pyridine derivatives has been prepared and evaluated as inotropic agents. The 1H-imidazo-[4,5-b] derivatives were found to be consistently more potent than their isomers in the [4,5-c] series in isolated guinea pig papillary muscle preparations. Structure-activity relationships and the species-dependence of inotropic potencies are discussed.