Synthesis of Novel trans-4-(Substituted-benzamido)-3,4-dihydro-2H-benzo[b]pyran-3-ol Derivatives as Potential Anticonvulsant Agents with a Distinctive Binding Profile

Chan, Wai N.; Evans, John; Hadley, Michael S.; Herdon, Hugh J.; Jerman, Jeffrey C.; Morgan, H. K. A.; Stean, Tania O.; Thompson, Mervyn; Upton, Neil; Vong, Antonio

doi:10.1021/jm960535w

Cited by 28 publications

(11 citation statements)

References 10 publications

(12 reference statements)

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“…22), showed good oral anticonvulsant activity when tested in the mouse by the MES threshold test. 249 The activity is mediated by the aforementioned distinctive binding site and the associated unique mechanism. SB 204269 has been selected for clinical evaluation as a pioneer treatment for epilepsy disorders because of the unique mechanistic nature of this class of anticonvulsants.…”

Section: Inhibitory Glycine Receptor Sitesmentioning

confidence: 99%

Molecular targets for the rational design of antiepileptic drugs and related neuroprotective agents

Lin¹,

Kadaba²

1997

Med. Res. Rev.

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Section: Inhibitory Glycine Receptor Sitesmentioning

confidence: 99%

Molecular targets for the rational design of antiepileptic drugs and related neuroprotective agents

Lin¹,

Kadaba²

1997

Med. Res. Rev.

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“…Tonabersat (SB‐220453) is a member of a family of novel benzoylamino‐benzopyran compounds, typified by carabersat (SB‐204269), which have potent anticonvulsant activity in a number of seizure models with potential for a good therapeutic ratio compared to other anticonvulsants ( Chan et al ., 1996 ; 1998 ; 1999 ; Herdon et al ., 1997 ; Upton et al ., 1997 ; Upton & Thompson, 2000 ). The pharmacology of this class of compound has been extensively investigated to demonstrate that they bind selectively to their own unique specific CNS binding site and have little effect on a variety of known anticonvulsant mechanisms ( Herdon et al ., 1996 ; 1997 ; Upton et al ., 1997 ; 1999 ; Upton & Thompson, 2000 ).…”

Section: Introductionmentioning

confidence: 99%

Tonabersat (SB‐220453) a novel benzopyran with anticonvulsant properties attenuates trigeminal nerve‐induced neurovascular reflexes

Parsons

Bingham

Raval

et al. 2001

British J Pharmacology

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1 The eects of tonabersat (SB-220453) were evaluated on trigeminal nerve ganglion stimulationinduced sensory-autonomic neurovascular re¯exes in the anaesthetized cat. Comparisons were made to intravenous administration of carabersat (SB-204269), and to valproate, gabapentin and lamotrigine following intraduodenal administration. 2 There were no eects on resting blood pressure, heart rate, carotid blood¯ow or carotid vascular resistance for any compound evaluated. 3 Trigeminal nerve ganglion stimulation increased carotid blood¯ow by 65% and reduced vascular resistance by 41% with minimal eect on blood pressure (510%) and no eect on heart rate. Intravenous infusion of tonabersat or carabersat (both 3.4 mmol h 71) produced time related reductions in stimulation-induced responses with a maximal inhibition (relative to control) of 30+7% (n=4), at 240 min for tonabersat and 33+4% (n=3) at 180 min for carabersat. Tonabersat (11.5 mmol h 71) produced a similar inhibitory eect (32+9%, n=4) after 120 min of infusion. 4 Following intraduodenal administration of tonabersat, the maximal inhibition of nerve stimulation-induced responses was 55+4% at 120 min (n=4) for tonabersat 10 mg kg 71, and 24+2% after 180 min for 1 mg kg 71 (n=4). 5 Intraduodenal administration of sodium valproate (10 or 100 mg kg 71 n=4/group) had no eect on neurovascular re¯exes. Maximal inhibition of nerve ganglion-stimulated reductions in carotid vascular resistance were observed at 150 min for lamotrigine (50 mg kg 71 , 52+12%, n=4) and gabapentin (100 mg kg 71 , 17+13%, n=3). Lamotrigine 10 mg kg 71 produced 22+11% (n=3) inhibition after 180 min. 6 These data demonstrate blockade of trigeminal parasympathetic re¯exes with tonabersat, carabersat and other anticonvulsants. These agents may therefore have therapeutic bene®t in conditions where this type of re¯ex is evident.

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“…It has potent oral anticonvulsant properties in a range of rat seizure models, with potency and efficacy equivalent to or better than carbamazepine and lamotrigine. Carabersat is currently being proposed for the treatment of epilepsy and migraine prophylaxis [33,34]. Subsequent exploration of structureactivity-relationships, using high-throughput screening of the novel SB-204269 binding site led to the identification of anticonvulsant active series of the isomeric tetrahydroisoquinolinyl (THIQ) benzamides 5-, 7-and 8-substituted [35,36].…”

Section: Heterocyclic Analogs Of Carabersatmentioning

confidence: 99%

New Anticonvulsant Agents

Malawska

2005

CTMC

144

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The search for antiepileptic compounds with more selective activity and lower toxicity continues to be an area of intensive investigation in medicinal chemistry. This review describes new anticonvulsant agents representing various structures for which the precise mechanism of action is still not known. Many of the compounds presented in this review have been tested according to the procedure established by the Antiepileptic Drug Development Program of the Epilepsy Branch of the National Institute of Neurological Disorders and Stroke, National Institute of Health, USA. The newer agents include sulfonamides, amino acids, amides (analogs of gamma-vinyl GABA, N-benzylamides, 2,6-dimethylanilides, carboxyamides, hydroxyamides, alkanoamides); heterocyclic agents ((arylalkyl)imidazoles, pyrrolidin-2,5-diones, lactams, semi- thiosemicarbazones, thiadiazoles, quinazolin-4(3H)-ones, 2,5-disubstituted 1,2,4-thadiazoles, xanthones, derivatives of isatin) and enaminones. These new structural classes of compounds can prove useful for the design of future targets and development of new drugs.

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Synthesis of Novel trans-4-(Substituted-benzamido)-3,4-dihydro-2H-benzo[b]pyran-3-ol Derivatives as Potential Anticonvulsant Agents with a Distinctive Binding Profile

Cited by 28 publications

References 10 publications

Molecular targets for the rational design of antiepileptic drugs and related neuroprotective agents

Molecular targets for the rational design of antiepileptic drugs and related neuroprotective agents

Tonabersat (SB‐220453) a novel benzopyran with anticonvulsant properties attenuates trigeminal nerve‐induced neurovascular reflexes

New Anticonvulsant Agents

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