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The variety of biological agents directed toward the tubulin system exceeds those acting on DNA, making it an important target for cancer chemotherapy. However, the complicated chemical structures and restricted access to the natural resources, in combination with the development of drug resistance, limit the first generation of natural products. Considerable efforts in the search and synthesis of new synthetic compounds, such as small molecular tubulin inhibitors, gave access to novel potential/promising drugs. Among these substances, two series of novel, easily accessible indole classes were identified as tubulin-destabilizing agents. Owing to the synthetic nature, potent in vitro and in vivo antitumoral activity, and efficacy against multidrug-resistant (MDR) tumors, D-24851 and D-64131 have significant potential in cancer treatment.

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3 Like 5-HT, anpirtoline concentration-dependently inhibited forskolin-stimulated adenylate cyclase activity in homogenates from the rat substantia nigra. Both effects were not additive, and could be prevented by 5-HTlB receptor antagonists such as propranolol and penbutolol.4 In superfused rat and pig brain cortex slices preincubated with [3H]-5-HT, the electrically evoked tritium overflow was inhibited by anpirtoline and 5-HT. Whereas 5-HT was equipotent in both tissues (EC50 = 69 nM), anpirtoline was markedly less potent in pig brain cortex slices (EC50 = 1190 nM) than in rat brain cortex slices (EC50 = 55 nM). The concentration-response curve for anpirtoline was shifted to the right by metitepine in both preparations. 5 In the social behaviour deficit test, anpirtoline and trifluoromethylphenyl-piperazine were effective in reversing the isolation-induced impairments in mice, an effect shown only by compounds with agonist properties at the 5-HTIB receptor.6 In the electrostimulated pain test using mice, anpirtoline dose-dependently increased the pain threshold with an ED50 of 0.52mgkg-1, i.p. The antinociceptive activity of anpirtoline was abolished by pretreatment with cyproheptadine or propranolol. 7 In the forced swimming test in rats, anpirtoline induced a dose-related increase in swimming activity. With an ED50 value of 4.6mgkg-1, i.p., anpirtoline was 4 times more potent than the two standard compounds imipramine and desipramine. The decrease of immobility time or the increase of active periods in this model of behavioural despair is suggested to be characteristic of ant-depressant drugs. 8 Anpirtoline exhibits both antinociceptive and antidepressant-like activities in animals. It is probable that anpirtoline elicits these pharmacological effects via its agonist effect on 5-HT1B and 5-HT1A receptors.

1 Flupirtine is a novel, centrally acting, non-opioid analgesic agent. The present investigation was undertaken to ascertain which neuronal systems might be responsible for its antinociceptive effect in rodents. The antinociceptive responses to the test compounds were examined in the tail-flick test. 2 The selective destruction of noradrenergic pathways by 6-hydroxydopamine considerably reduced the flupirtine-induced inhibition of nociceptive responses but not the clonidine-induced antinociception which was significantly enhanced. Depletion of spinal 5-hydroxytryptaminergic pathways by pretreatment with 5,7-dihydroxytryptamine failed to affect the action of flupirtine and clonidine.3 The depletion of neurotransmitters by reserpine totally abolished the antinociceptive action of flupirtine. By contrast, clonidine-induced inhibition of nociceptive responses remained unchanged. 4 Inhibition of the synthesis of noradrenaline by a-methyl-L-p-tyrosine attenuated the antinociception induced by flupirtine. In contrast, inhibition of the synthesis of 5-hydroxytryptamine by (±)6-fluorotryptophan did not influence the antinociceptive activity of flupirtine. 5 Inhibition of noradrenaline uptake by imipramine led to a significant augmentation of flupirtine-induced antinociception. 6 Selective antagonists at a-adrenoceptors significantly decreased the antinociceptive action of flupirtine. Antinociception induced by clonidine was significantly diminished by idazoxan but not by prazosin. 7 The 5-hydroxytryptamine (5-HT) antagonist, ketanserin diminished the antinociceptive activity of flupirtine, probably due to its additional a,-adrenoceptor antagonist activity. The antinociceptive effect of clonidine was not influenced by ketanserin.8 Cholinoceptor antagonists such as mecamylamine and pirenzepine did not alter the antinociceptive action of flupirtine. Flupirtine-induced antinociception also remained unchanged after pretreatment with haloperidol. 9 Flupirtine has no pharmacologically relevant affinity for ac-, CX2-adrenoceptors, 5-HT1-and 5-HT2-receptors as shown in direct binding studies. 10 The present results indicate that the antinociceptive action induced by flupirtine depends on the descending noradrenergic pain-modulating system.