Maria H. Paluchowska

Arene- and quinoline-sulfonamides as novel 5-HT7 receptor ligands

Novel arene- and quinolinesulfonamides were synthesized using different solutions and a solid-support methodology, and were evaluated for their affinity for 5-HT(1A), 5-HT(2A), 5-HT(6), and 5-HT(7) receptors. Compound 54 (N-Ethyl-N-[4-(1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-2-yl)butyl]-8-quinolinesulfonamide) was identified as potent 5-HT(7) antagonist (K(i)=13 nM, K(B)=140 nM) with good selectivity over 5-HT(1A), 5-HT(2A), 5-HT(6) receptors. In the FST in mice, it reduced immobility in a manner similar to the selective 5-HT(7) antagonist SB-269970.

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.

Crystal and Molecular Structure of 4-[ω-(Benzotriazolyl)alkyl]-1-(2-methoxyphenyl)piperazines with a Different Pharmacological Activity

The crystal structure of six 4‐[ω‐(benzotriazolyl)alkyl]‐1‐(2‐methoxyphenyl)piperazine hydrochlorides 1–6 with a similar in vitro but different in vivo activity has been solved. A conformational analysis of free bases by Random Search and AM1 methods has been performed. Molecular electrostatic potential distribution (MEP) and dipole moments for the optimized crystallographic structures and global energy minimum conformations were calculated. Crystallographic data, as well as the conformational analysis indicated that the investigated compounds can adopt a variety of conformations of small energy difference. The effect of conformational changes on MEP was discussed.