Almost all tested compounds (except 3l and 3p) and to varying degrees (the strongest effect for 3n compound, p < 0.001) suppressed L-5-HTP-induced head-twitch episodes (Fig. 8), suggesting some connections with serotonin system. The tested substances failed to protect against clonic seizures, tonic convulsions, and death in PTZ-induced model of seizures. Fig. 8 The influence of the tested compounds on the head-twitch responses evoked by L-5-HTP (230 mg/kg). The results are expressed as mean ± SEM of a group of eight mice. One-way ANOVA showed significant changes in the number of head-twitch episodes (F 7,56 = 4.879, p < 0.001). The post-hoc Tukey’s test confirmed a significant decrease
in the numer of head-twitch episodes after the administration of the following compounds AZD6244 mw in the dose of 0.1 ED50: 3n (p < 0.001), 3d (p < 0.01), and 3a, 3g, and 3s (p < 0.05) The results of the pharmacological investigation showed that both investigated series exerted significant influence on the central nervous system of laboratory animals.
The most important seems to be their strong CNS this website depressive, antinociceptive, and serotonergic effects. The observed effects on the CNS of mice seem to be connected primarily with serotonergic neurotransmission, since almost all compounds (except 3l, 3p) inhibited significantly L-5-HTP-induced head-twitches. The drug-elicited head-twitch response (HTR) (Corne et al., RepSox ic50 1963; Corne and Pickering, 1967) is a selective behavioral model for 5-HT2 agonist activity in rodents, and several previous studies have established that direct and indirect 5-HT agonists induce this effect (Colpaert and Janssen, 1983; Darmani et al., 1990a, b, 1992; Fantegrossi et al., 2004; Peroutka et al., 1981). Furthermore, 5-HT2 receptor antagonists selectively block HTR (Fantegrossi et al., 2004; Handley and Singh, 1986; Lucki Miconazole et al., 1984), and their potency is highly correlated with the antagonist’s affinity for 5-HT2 receptors (Ortmann et al., 1982; Peroutka et al., 1981). In addition, most of the tested compounds
inhibited the motility of animals and changed body temperature of normothermic mice, which also may confirm the involvement of serotonin system. Structure–activity relationship The lack of activity of compound 3l may be connected with the low blood–brain permeation. Furthermore, the presence of benzyl not phenyl substituent at the nitrogen N1 atom orients the pharmacophoric aromatic ring differently and it may constitute another explanation of the lack of acivity of 3l. In order to further investigate the lack of activity of this componds, some structural and electronic parameters were calculated (Table 3). Compounds 3l and 3x have the greatest value of HOMO–LUMO gap. Furthermore, the map of HOMO and LUMO orbitals for the inactive compound 3l is slightly different than for the acive compound 3a (Fig. 9).