Anna Wesołowska

Effect of the selective 5-HT7 receptor antagonist SB 269970 in animal models of anxiety and depression

The aim of the present study was to examine the effect of the selective 5-HT7 receptor antagonist SB 269970 (0.25-20 mg/kg) in the behavioral tests commonly used for predicting anxiolytic- and antidepressant-like activity. Diazepam and imipramine were used as standard drugs. SB 269970 (in one medium dose of 0.5 or 1 mg/kg) exerted a specific antianxiety-like effect in the Vogel drinking test in rats, in the elevated plus-maze test in rats and in the four-plate test in mice. Moreover, SB 269970 (in one medium dose of 5 or 10 mg/kg) showed antidepressant-like activity in the forced swimming and the tail suspension tests in mice. At the same time, the tested compound at doses of 1-20 mg/kg did not change the spontaneous locomotor activity of mice. The potential anxiolytic and antidepressant effects produced by SB 269970 were weaker than those of the reference drugs employed. It is noteworthy that the active doses of SB 269970 were devoid of any visible motor side-effects. In conclusion, the results of our studies indicate that 5-HT7 receptor antagonists may play a role in the therapy of both anxiety and depression.

Effects of the brain-penetrant and selective 5-HT6 receptor antagonist SB-399885 in animal models of anxiety and depression

The effects of a selective 5-HT(6) receptor antagonist, SB-399885 (N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide), were evaluated in behavioural tests sensitive to clinically effective anxiolytic- and antidepressant-compounds using diazepam and imipramine as reference drugs. In the Vogel conflict drinking test in rats, SB-399885 (1-3mg/kg i.p.) caused an anxiolytic-like activity comparable to that of diazepam (2.5-5mg/kg i.p.). An anxiolytic-like effect was also seen in the elevated plus-maze test in rats, where SB-399885 (0.3-3mg/kg i.p.) was slightly weaker than diazepam (2.5-5mg/kg i.p.). In the four-plate test in mice, SB-399885 (3-20mg/kg i.p.) showed an anxiolytic-like effect which was weaker than that produced by diazepam (2.5-5mg/kg i.p.). In the forced swim test in rats, SB-399885 (10mg/kg i.p.) significantly shortened the immobility time and the effect was stronger than that of imipramine (30mg/kg i.p.). In the forced swim test in mice, SB-399885 (20-30mg/kg i.p.) had an anti-immobility action, comparable to imipramine (30mg/kg i.p.) and also in the tail suspension test in mice, SB-399885 (10-30mg/kg i.p.) had an antidepressant-like effect, though was weaker than imipramine (10-20mg/kg i.p.). The tested 5-HT(6) antagonist (3-20mg/kg i.p.) shortened the walking time of rats in the open field test and, at a dose of 30mg/kg i.p. reduced the locomotor activity of mice. SB-399885 (in doses up to 30mg/kg i.p.) did not affect motor coordination in mice and rats tested in the rota-rod test. Such data indicate that the selective 5-HT(6) receptor antagonist SB-399885had specific effects, indicative of this compounds anxiolytic and antidepressant potential.

Anxiolytic-like and antidepressant-like effects produced by the selective 5-HT6 receptor antagonist SB-258585 after intrahippocampal administration to rats.

The purpose of this study was to investigate the effect of SB-258585, a selective 5-HT6 receptor antagonist, administered intrahippocampally to rats, in the conflict drinking and forced swim tests, that is models used for evaluating anxiolytic-like and antidepressant-like activity, respectively. Diazepam and imipramine were used as reference drugs. SB-258585 at a dose of 1 μg (but not 0.3 and 3 μg) showed an anticonflict effect that was weaker than that of diazepam (40 μg). SB-258585 at a dose of 3 μg (but not 1 and 10 μg) produced a marked anti-immobility effect comparable with that of imipramine (0.1 μg). The anxiolytic-like and antidepressant-like activity of SB-258585 seemed to be specific, as that compound − when given by the same route in doses effective in each model – did not affect the shock threshold, nonpunished water consumption, or exploratory activity of rats. The results obtained indicate that the hippocampus is one of the neuroanatomical sites involved in the anxiolytic-like and antidepressant-like activity of the selective 5-HT6 receptor antagonist SB-258585.

The selective 5-HT6 receptor antagonist SB-399885 enhances anti-immobility action of antidepressants in rats

The aim of the present study was to investigate the effect of antidepressant drugs (characterized by a different mechanism of action), administered jointly with the selective 5-HT(6) receptor antagonist N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide (SB-399885), in the forced swim test in rats. All the compounds under study were given intraperitoneally in doses which did not shorten the immobility time of rats. Co-administration of SB-399885 (3 mg/kg) and imipramine (20 mg/kg), desipramine (20 mg/kg), bupropion (5 mg/kg) or moclobemide (20 mg/kg), produced significant anti-immobility action, whereas SB-399885 (3 mg/kg) given jointly with citalopram (20 mg/kg) did not affect immobility time. None of the compounds studied, given alone or jointly, increased the general activity of rats measured in the open field test. The obtained results indicate that the blockade of 5-HT(6) receptors may facilitate the anti-immobility effect of imipramine, desipramine, bupropion or moclobemide in the forced swim test.

Active conformation of some arylpiperazine postsynaptic 5-HT1A receptor antagonists

The synthesis and pharmacological properties of novel conformationally restricted arylpiperazine (2b-4b) or 1,2,3,4-tetrahydroisoquinoline (5b and 6b) derivatives of the known, flexible 5-HT(1A) receptor ligands 2a-6a (K(i)=0.95-7 nM) with different intrinsic activities are reported. Replacement of a tetramethylene chain with a 1e,4e-disubstituted cyclohexane ring in the structure of flexible ligands resulted in insignificant diminution of the 5-HT(1A) receptor affinity in the case of 2b-4b (K(i)=15-52 nM), whereas derivatives 5b and 6b were practically inactive (K(i)>1354 nM). The results of in vivo behavioural tests showed that 2a and 3a acted as postsynaptic 5-HT(1A) receptor partial agonists. Like the flexible 4a, the new rigid compounds 2b-4b showed features of postsynaptic 5-HT(1A) receptor antagonists. Since all possible conformations of the constrained compounds belong to an extended family--as indicated by molecular modelling studies--our hypothesis that such conformations are responsible for the blockade of postsynaptic 5-HT(1A) receptors has been confirmed. Determination of regions explored by terminal amide, or imide and hydrocarbon groups of the restricted compounds as well as the results of in vitro and in vivo studies allowed us to discuss the bioactive conformations of flexible ligands.

Involvement of presynaptic 5-HT1A and benzodiazepine receptors in the anticonflict activity of 5-HT1A receptor antagonists

In the present paper, we examined the effect of lesions of 5-hydroxytryptamine (5-HT) neurons, produced by p-chloroamphetamine (p-CA; 2 x 10 mg/kg), and the influence of flumazenil (Ro 15-1788, 10 mg/kg), a benzodiazepine receptor antagonist, on the anticonflict activity of N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY 100635) and trans-1-(2-methoxy-phenyl)-4-[4-succinimidocyclohexyl]piperazine (MP 349), pre- and postsynaptic 5-HT(1A) receptor antagonists, and 1-(2-methoxyphenyl)-4-(4-succinimidobutyl)piperazine (MM 77), a postsynaptic 5-HT(1A) receptor antagonist, in the Vogel conflict drinking test in rats. Diazepam was used as a reference compound. WAY 100635 (0.5-1 mg/kg), MP 349 (0.25-0.5 mg/kg), MM 77 (0.03-0.25 mg/kg) and diazepam (2.5-5 mg/kg) significantly increased the number of shocks accepted during experimental sessions in the conflict drinking test. In p-chloroamphetamine-pretreated rats, neither WAY 100635 (1 mg/kg) nor MP 349 (0.25 mg/kg) induced an anticonflict effect, whereas MM 77 (0.06 mg/kg) did produce it. Flumazenil fully blocked the anticonflict effects of WAY 100635 (1 mg/kg) and diazepam (5 mg/kg), and it partly but significantly reduced the anticonflict effects of MP 349 (0.25 mg/kg) and MM 77 (0.06 mg/kg). p-Chloroamphetamine and flumazenil alone were inactive in the conflict drinking test. The present results suggest that, first, the anticonflict effect of the 5-HT(1A) receptor antagonists, WAY 100635 and MP 349, but not MM 77, is linked to the presynaptically located 5-HT(1A) receptors, and second, benzodiazepine receptors are indirectly involved in such effects of WAY 100635, MP 349 and MM 77, due maybe to a possible interaction between the 5-HT and the gamma-aminobutyric acid (GABA)/benzodiazepine systems.

Pharmacological characterization of MP349, a novel 5-HT1A-receptor antagonist with anxiolytic-like activity, in mice and rats.

The purpose of this study was to further characterize the pharmacological effects of MP349 (trans‐1‐(2‐methoxyphenyl)‐4‐(4‐succinimidocyclohexyl)piperazine), a new serotonin 5‐HT1A postsynaptic receptor antagonist, using several biochemical and behavioural assays. The silent 5‐HT1A‐receptor antagonist WAY 100635 (N‐{2‐[4‐(2–1‐piperazinyl]ethyl)‐N‐pyridinyl)cyclohexanecarboxamide) was used as a reference compound in in‐vivo tests, and diazepam served as standard anxiolytic drug in animal models of anxiety. In this study we showed that MP349 bound with moderate affinity (Ki = 234 nm) for α‐adrenoceptors, and with very low affinity (Ki > 2600 nm) for 5‐HT2A, dopamine D1, D2 and benzodiazepine receptors. The effects of MP349 on presynaptic 5‐HT1A receptors were studied in two models (mice and rats). Like WAY 100635, MP349 antagonized the hypothermia induced by the 5‐HT1A‐receptor agonist 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin(8‐OH‐DPAT) in mice. Neither MP349 nor WAY 100635 administered alone induced hypothermia. In a rat microdialysis study, MP349 (like WAY 100635) did not affect 5‐HT dialysate level in the prefrontal cortex; however, when given before 8‐OH‐DPAT, it inhibited the decrease in 5‐HT release induced by the 5‐HT1A agonist. The data demonstrated that MP349 behaved like a functonal antagonist of presynaptic 5‐HT1A receptors. The potential anxiolytic activity of MP349 and reference drugs was examined in a conflict drinking test in rats, a plus‐maze test in rats and a four‐plate test in mice. MP349 and WAY 100635 produced anxiolytic‐like effects, though somewhat weaker than those induced by diazepam, and only in the case of diazepam the anxiolytic‐like effects were dose‐dependent. Moreover, MP349 administered in doses inducing anxiolytic‐like effects did not disturb the locomotor activity (open field test) or locomotor coordination (rota‐rod test) of rats. These and earlier results indicated that MP349 was an antagonist of 5‐HT1A receptors which exhibited anxiolytic‐like activity in an animal model of anxiety.

The influence of substitution at aromatic part of 1,2,3,4-tetrahydroisoquinoline on in vitro and in vivo 5-HT1A/5-HT2A receptor activities of its 1-adamantoyloaminoalkyl derivatives

Further structure-activity relationship (SAR) studies with the 1,2,3,4-tetrahydroisoquinoline (THIQ) class of 5-HT(1A) ligands led to the synthesis of new 1-adamantoyloaminoalkyl derivatives. The impact of substituent variations in the aromatic part of THIQ moiety on 5-HT(1A) and 5-HT(2A) receptor affinities, as well as in vivo functional properties of the investigated compounds were discussed. It was found that those modifications reduced the binding affinity for 5-HT(1A) receptors (in comparison with unsubstituted THIQ derivatives); however, the majority of new compounds still remained potent 5-HT(1A) ligands (K(i)=4.9-46 nM) and most of them showed features of partial agonists of postsynaptic 5-HT(1A) receptors. At the same time, their 5-HT(2A) receptor affinity was slightly increased (K(i)=40-1475 nM), which resulted in a loss of 5-HT(2A)/5-HT(1A) selectivity. 5-Br,8-OCH3 derivative-the most potent, mixed 5-HT(1A)/5-HT(2A) ligand-produced activation of presynaptic 5-HT(1A) receptors and showed properties of a 5-HT(2A) receptor antagonist.