Newer N-phthaloyl GABA derivatives with antiallodynic and antihyperalgesic activities in both sciatic nerve and spinal nerve ligation models of neuropathic pain.

BACKGROUND: There is considerable research evidence supporting a palliative role for gamma-aminobutyric acid (GABA)-ergic neurotransmission and voltage-gated sodium channel blockade in neuropathic pain conditions. Hence, the present study was undertaken to assess the peripheral analgesic, antiallodynic and antihyperalgesic activities of the synthesized structural analogues of GABA. METHODS: The screening study included acute tissue injury, chronic constriction injury (CCI), and spinal nerve ligation (SNL) models of neuropathic pain. RESULTS: All of the tested compounds sup-pressed the acetic acid-induced writhing response significantly in comparison to the control. In particular, compound JVP-8 was observed to be the most active compound with percent inhibition greater than that of the standard drug aspirin (97.8% inhibition of writhing response as against 97.0% shown by aspirin). In neuropathic pain studies, compound JVP-5 (100 mg/kg i.p.) emerged as the most active compound affording maximum protection against dynamic allodynia and mechanical hyperalgesia in the CCI model, and against spontaneous pain and mechanical hyperalgesia in SNL rats. CONCLUSION: In this study, we have demonstrated that combining phthalimide pharmacophore with GABA has evolved compounds effective for the treatment of neuropathic pain.

Discovery of 4-aminobutyric acid derivatives possessing anticonvulsant and antinociceptive activities: a hybrid pharmacophore approach.

Antiepileptic drugs are often utilized in the treatment of neuropathic pain. The present study aims at the design and synthesis of newer gamma-aminobutyric acid (GABA) derivatives with the combination of aryl semicarbazone and the GABA pharmacophores in order to develop a multifunctional drug useful in the treatment of neurological disorders like epilepsy and neuropathic pain. Various GABA semicarbazones were synthesized and screened for anticonvulsant, peripheral analgesic, antiallodynic, and antihyperalgesic activities. The structures of the synthesized compounds were confirmed by the use of their spectral data in addition to elemental analysis. The synthesized derivatives of the inhibitory neurotransmitter GABA produced anticonvulsant and antinociceptive actions in the acetic acid induced writhing test and peripheral nerve injury (chronic constriction injury and L5 spinal nerve ligation) models of neuropathic pain. The underlying mechanisms are expected to be enhancement of peripheral GABAergic neurotransmission owing to their activity in the scPIC screen and due to various reports on the involvement of GABAergic pathway in peripheral models of neuropathic pain.

Nitric oxide synthase regulation and diversity: implications in Parkinson's disease.

Nitric oxide (NO) is a janus faced chemical messenger, which, in the recent years, has been the focus of neurobiologists for its involvement in neurodegenerative disorders in particular, Parkinson's disease (PD). Nitric oxide synthase, the key enzyme involved in NO production exists in three known isoforms. The neuronal and inducible isoforms have been implicated in the pathogenesis of PD. These enzymes are subject to complex expressional and functional regulation involving mRNA diversity, phosphorylation and protein interaction. In the recent years, mRNA diversity and polymorphisms have been identified in the NOS isoforms. Some of these genetic variations have been associated with PD, indicating an etiological role for the NOS genes. This review mainly focuses on the NOS genes - their differential regulation and genetic heterogeneity, highlighting their significance in the pathobiology of PD.

Synthesis of N4-(2,4-dimethylphenyl) semicarbazones as 4-aminobutyrate aminotransferase inhibitors.

Several 2,4-dimethylphenyl substituted semicarbazones were synthesized in three steps involving aryl urea and aryl semicarbazide formation. The structures were confirmed by spectral and elemental analyses. All the compounds were evaluated for anticonvulsant activity by using a series of test models, including maximal electroshock seizure, subcutaneous pentylenetetrazole and subcutaneous strychnine seizure threshold tests. The compounds were also evaluated for behavioural impairement and depression activity. In the neurochemical investigation, potent compounds were evaluated for their effects on rat brain gamma-aminobutyric acid (GABA) levels and in vitro gamma-aminobutyrate transaminase (Pseudomonas fluorescens) activity. Preliminary studies suggest that these compounds exhibit anticonvulsant activity via a GABA-mediated mechanism.

Synthesis and in-vitro cytotoxicity evaluation of gatifloxacin Mannich bases.

Mannich bases of gatifloxacin were synthesized by reacting them with formaldehyde and several isatin derivatives. Their chemical structures have been confirmed by means of their IR, 1H-NMR data and by elemental analysis. The compounds were tested in-vitro against a panel of 58 human tumour cell lines derived from nine neoplastic diseases. Among them compound 1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-7[[N4-(3'-sulphadoximino)-1'-(5-bromoisatinyl) methyl]-3-methyl N1-piperazinyl]-3-quinoline carboxylic acid (6) emerged as a potent anticancer agent being more active than standard DNA topoisomerase II inhibitor, etoposide against 30 cancer cell lines.

3-Chloro-2-methylphenyl-substituted semicarbazones: synthesis and anticonvulsant activity.

A series of 3-chloro-2-methylphenyl substituted semicarbazones (3-33) was synthesized and evaluated for anticonvulsant and CNS activities. After intraperitoneal injection to mice or rats, the semicarbazone derivatives were examined in the maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ), and subcutaneous strychnine (scSTY)-induced seizure and neurotoxicity screens. The aryl urea (1) and the semicarbazide (2) showed anticonvulsant activity in the MES and scPTZ screens with acute neurotoxicity, whereas the semicarbazone derivatives showed good anticonvulsant potency in the scSTY screen with moderate activity against MES and scPTZ screens. Compound 21 exhibited anticonvulsant potency against all the three screens with lesser neurotoxicity. Some titled compounds exhibited lesser CNS depression and neurotoxicity compared to phenytoin or carbamazepine as was evident from the CNS studies.