Profile of SB‐204269, a mechanistically novel anticonvulsant drug, in rat models of focal and generalized epileptic seizures

Abstract

1 Earlier optimization of structure-activity relationships in a novel series of 4-(benzoylamino)-benzopyrans, led to the discovery of SB-204269 (trans-(+)-6-acetyl-4S-(4-¯uorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-benzo [b]pyran-3R-ol, hemihydrate), a potent orally-active anticonvulsant in the mouse maximal electroshock seizure threshold (MEST) test. 2 Studies have now been undertaken to determine the e ects of SB-204269 in a range of seizure models and tests of neurological de®cits in rats. In addition, the compound has been evaluated in a series of in vitro mechanistic assays. 3 SB-204269 proved to be an orally-e ective anticonvulsant agent, at doses (0.1 ± 30 mg kg 71 ) devoid of overt behavioural depressant properties, in models of both electrically (MEST and maximal electroshock (MES)) and chemically (i.v. pentylenetetrazol (PTZ) infusion)-evoked tonic extension seizures. However, the compound did not inhibit PTZ-induced myoclonic seizures at doses up to 30 mg kg 71 , p.o. 4 SB-204269 also selectively reduced focal electrographic seizure activity in an in vitro elevated K + rat hippocampal slice model at concentrations (0.1 ± 10 mM) that had no e ect on normal synaptic activity and neuronal excitability. 5 In all of these seizure models, SB-204269 was equivalent or better than the clinically established antiepileptic drugs carbamazepine and lamotrigine, in terms of anticonvulsant potency and e cacy. 6 Unlike SB-204269, the corresponding trans 3S,4R enantiomer, SB-204268, did not produce marked anticonvulsant e ects, an observation in accord with previous ®ndings for other related pairs of trans enantiomers in the benzopyran series. 7 In the rat accelerating rotarod test, a sensitive paradigm for the detection of neurological de®cits such as sedation and motor incoordination, SB-204269 was inactive even at doses as high as 200 mg kg 71 , p.o. This was re¯ected in the excellent therapeutic index (minimum signi®cantly e ective dose in the rotarod test/ED 50 in the MES test) for SB-204269 of 431, as compared to equivalent values of only 7 and 13 for carbamazepine and lamotrigine, respectively. 8 At concentrations (510 mM) well above those required to produce anticonvulsant activity in vivo (i.e. 0.1 mM in brain), SB-204269 did not interact with many of the well known mechanistic targets for established antiepileptic drugs (e.g. Na + channels or GABAergic neurotransmission). Subsequent studies have shown that the anticonvulsant properties of SB-204269 are likely to be mediated by a novel stereospeci®c binding site present in the CNS. 9 The overall e cacy pro®le in rodent seizure models, together with a minimal liability for inducing neurological impairment and an apparently unique mechanism of action, highlight the therapeutic potential of SB-204269 for the treatment of refractory partial and generalized tonic-clonic seizures.

The Efficacy of Sodium Channel Blockers to Prevent Phencyclidine-Induced Cognitive Dysfunction in the Rat: Potential for Novel Treatments for Schizophrenia

“…A final aim of the present study was to assess the potential of the new sodium channel blockers to produce centrally mediated side effects typical of their class (for example, sedation, muscle relaxation, and motor incoordination) (Upton et al, 1997). The measurement of an animal's basal activity in a novel environment allows the assessment of these adverse effects (Helton et al, 1998).…”

Molecular Targets for Antiepileptic Drug Development

“…Recent evidence implicating astrocytes in the generation of epileptic activity suggest that selective targeting of astrocytic gap junctions, such as Cx43, may be a fruitful strategy. 418 The novel benzoylamino benzopyran tonabersat [SB-220453; an analog of the anticonvulsant carabersat (SB-204269) 419 ], which is currently in clinical development for migraine, is believed to block gap junctions. 420 …”

Evidence for a Selective Role of the δ-Opioid Agonist [8R-(4bS*,8aα,8aβ,12bβ)]7,10-Dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl 5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline Hydrochloride (SB-235863) in Blocking Hyperalgesia Associated with Inflammatory and Neuropathic Pain Responses

“…Assessment of potential proconvulsant or anticonvulsant effects of SB-235863 was made as previously described by Upton et al (1997). Results of the maximal electroshock seizure test were expressed as CC 50 values, i.e., the threshold current required for the induction of tonic hindlimb extension seizures.…”