Synthesis and metabolic profile of Cl‐966: A potent, orally‐active inhibitor of GABA uptake

Bjorge, S. M.; Black, Ann E.; Bockbrader, Howard N.; Chang, Tsun; Gregor, V.; Lobbestael, Sandra J.; Nugiel, David A.; Pavia, Michael R.; Radulovic, Louis L.; Woolf, Thomas F.

doi:10.1002/ddr.430210305

Cited by 21 publications

(12 citation statements)

References 15 publications

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“…In addition, nipecotic acid is itself a substrate for the GABA uptake carrier and can be re-released in a calciumdependent manner on further neuronal depolarization and thus act as a false transmitter (Larsson et al, 1983;Krogsgaard-Larsen et al, 1987). Yunger et al (1984), Braestrup et al (1987Braestrup et al ( , 1990, Bjorge et al (1990), Nielsen et al (1991), and Andersen et al (1993) described novel series of lipophilic GABA uptake inhibitors that show potent activity in vitro and in vivo. These compounds differ from nipecotic and similar cyclic amino acid GABA uptake inhibitors (Krogsgaard-Larsen and Johnston, 1975) in that they readily cross the BBB due to increased lipophilicity after substitution of a lipophilic anchor on the amino acid nitrogen atom.…”

Section: Overview Of Gaba Neurotransmissionmentioning

confidence: 99%

A Review of the Preclinical Pharmacology of Tiagabine: A Potent and Selective Anticonvulsant GABA Uptake Inhibitor

1995

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We review the neurochemical and behavioral profile of the selective gamma-aminobutyric acid (GABA) uptake inhibitor, (R)-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl) nipecotic acid hydrochloride [tiagabine (TGB), previously termed NNC 05-0328, NO 05-0328, and NO-328], which is currently in phase III clinical trials for epilepsy. TGB is a potent, and specific GABA uptake inhibitor. TGB lacks significant affinity for other neurotransmitter receptor binding sites and/or uptake sites. In electrophysiological experiments in hippocampal slices in culture, TGB prolonged the inhibitory postsynaptic potentials (IPSP) and inhibitory postsynaptic currents (IPSC) in the CA1 and CA3 produced by the addition of exogenous GABA. In vivo microdialysis shows that TGB also increases extracellular GABA overflow in a dose-dependent manner. Together these biochemical data suggest that the in vitro and in vivo mechanism of action of TGB is to inhibit GABA uptake specifically, resulting in an increase in GABAergic mediated inhibition in the brain. TGB is a potent anticonvulsant agent against methyl-6,7-dimethyoxy-4-ethyl-B-carboline-3-carboxylate (DMCM)-induced clonic convulsions (mice), subcutaneous pentylenetetrazol (PTZ)-induced tonic convulsions (mice and rats), sound-induced convulsions in DBA/2 mice and genetically epilepsy-prone rats (GEPR), and electrically induced convulsions in kindled rats. TGB is partially efficacious, against subcutaneous PTZ-induced clonic convulsions, and photically induced myoclonus in Papio papio. TGB is weakly efficacious in the intravenous PTZ seizure threshold test and the maximal electroshock seizure (MES) test and produces only partial protection against bicuculline (BIC)-induced convulsions in rats. The overall biochemical and anticonvulsant profile of TGB suggests potential utility in the treatment of chronic seizure disorders such as generalized clonic-tonic epilepsy (GTCS), photomyoclonic seizures, myoclonic petit mal epilepsy, and complex partial epilepsy.

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Section: Overview Of Gaba Neurotransmissionmentioning

confidence: 99%

A Review of the Preclinical Pharmacology of Tiagabine: A Potent and Selective Anticonvulsant GABA Uptake Inhibitor

1995

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“…(9)) [96]. Examples are SKF 89976A, SKF 100330A [97], tiagabine ((R)-N-[4,4-di(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid) [98], NC-711 [99] and CI-966 [100], which have a suitable lipophilicity to enter the central nervous system after oral administration, are potent inhibtors of GABA uptake, and proved protective against seizures in some animal models. In addition, SKF 89976A, tiagabine, NC-711, and CI-966 are highly selective for GAT-1 [101].…”

Section: Gaba Transportermentioning

confidence: 98%

The Inhibitory Neural Circuitry as Target of Antiepileptic Drugs

Böhme¹,

Lüddens²

2001

CMC

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Impairments and defects in the inhibitory neurotransmission in the CNS can contribute to various seizure disorders, i.e., gamma-aminobutyric acid (GABA) and glycine as the main inhibitory neurotransmitters in the brain play a crucial role in some forms of epilepsy. Recent advances in deciphering the molecular basis of the GABAergic and glycinergic systems has been achieved by means of cloning techniques and gene targeting strategies in animals, contributing to the understanding of drug action. As well, several anticonvulsive substances emerged which target key molecules of the inhibitory systems. Employment of recombinant expression systems, including, but not restricted to the inhibitory circuitry, will further facilitate drug screening and rational approaches to design novel specific antiepileptic drugs, which act highly efficiently to prevent or reduce generation and spread of seizures.

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“…LAT-1 is important because it transports several prescription drugs, such as the antiparkinsonian drug L-dopa and the anticonvulsant gabapentin, across the BBB, thereby enabling their pharmacologic effects [10,11]. This function at the BBB has made LAT-1 a target for drug delivery by modifying CNS-impermeable drugs such that they become LAT-1 substrates and have enhanced BBB penetration [12][13][14][15].…”

Section: Design Considerationmentioning

confidence: 99%

“…Nipecotic acid fails to cross the BBB owing to its polar and zwitterionic nature. The potential antiepileptic activity of nipecotic acid coupled with its synthetic versatility has led to the synthesis of a vast number of structurally diverse lipophilic derivatives with marked antiepileptic activity [6][7][8][9][10][11][12][13]. It has been found that substances crossing the BBB through many pathways (Transmembrane diffusion, Carrier mediated-transport and transcytosis).…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Enhanced BBB Penetration Studies of L-serine-Tethered Nipecotic Acid-Prodrug

et al. 2020

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Nipecotic acid is considered to be one of the most potent inhibitors of neuronal and glial-aminobutyric acid (GABA) uptake in vitro. Due to its hydrophilic nature, nipecotic acid does not readily cross the blood-brain barrier (BBB). Large neutral amino acids (LAT1)-knotted nipecotic acid prodrug was designed and synthesized with the aim to enhance the BBB permeation by the use of carrier-mediated transport. The synthesized prodrug was tested in animal models of Pentylenetetrazole (PTZ)-induced convulsions in mice. Further pain studies were carried out followed by neurotoxicity estimation by writhing and rota-rod test respectively. HPLC data suggests that the synthesized prodrug has improved penetration through BBB. Nipecotic acid-L-serine ester prodrug with considerable anti-epileptic activity, and the ability to permeate the BBB has been successfully synthesized. Graphical Abstract.

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Synthesis and metabolic profile of Cl‐966: A potent, orally‐active inhibitor of GABA uptake

Cited by 21 publications

References 15 publications

A Review of the Preclinical Pharmacology of Tiagabine: A Potent and Selective Anticonvulsant GABA Uptake Inhibitor

A Review of the Preclinical Pharmacology of Tiagabine: A Potent and Selective Anticonvulsant GABA Uptake Inhibitor

The Inhibitory Neural Circuitry as Target of Antiepileptic Drugs

Design, Synthesis and Enhanced BBB Penetration Studies of L-serine-Tethered Nipecotic Acid-Prodrug

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