Beata Duszyńska

Quinoline- and isoquinoline-sulfonamide derivatives of LCAP as potent CNS multi-receptor-5-HT1A/5-HT2A/5-HT7 and D2/D3/D4-agents: the synthesis and pharmacological evaluation.

Two series of arylpiperazinyl-alkyl quinoline-, isoquinoline-, naphthalene-sulfonamides with flexible (13-26) and semi-rigid (33-36) alkylene spacer were synthesized and evaluated for 5-HT(1A), 5-HT(2A), 5-HT(6), 5-HT(7) and selected compounds for D(2), D(3), D(4) receptors. The compounds with a mixed 5-HT and D receptors profile 16 (N-{4-[4-(3-chlorophenyl)-piperazin-1-yl]-butyl}-3-quinolinesulfonamide) and 36 (4-(4-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethyl}-piperidine-1-sulfonyl)-isoquinoline), displaying antagonistic activity at 5-HT(7), 5-HT(2A), D(2) postsynaptic sites, produced antidepressant-like effects in the forced swim test in mice and showed significant anxiolytic activity in the plus-maze test in rats. The lead compound 36, a multi-receptor 5-HT(2A)/5-HT(7)/D(2)/D(3)/D(4) agent, also displayed significant antipsychotic properties in the MK-801-induced hyperlocomotor activity in mice.

Antidepressant and antipsychotic activity of new quinoline- and isoquinoline- sulfonamide analogs of aripiprazole targeting serotonin 5-HT1A/5-HT2A/5-HT7 and dopamine D2/D3 receptors

A series of new quinoline- and isoquinoline-sulfonamide analogs of aripiprazole was synthesized to explore the influence of two structural features - replacement of ether/amide moiety with sulfonamide one, and localization of a sulfonamide group in the azine moiety. In contrast to aripiprazole, compound 33 (N-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)quinoline-7-sulfonamide) and 39 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)isoquinoline-3-sulfonamide) displaying multireceptor 5-HT(1A)/5-HT(2A)/5-HT(7)/D(2)/D(3) profile, and behaving as 5-HT(1A) agonists, D(2) partial agonists, and 5-HT(2A)/5-HT(7) antagonists, produced significant antidepressant activity in FST in mice. On the other hand, their 4-isoquinolinyl analog 40 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)isoquinoline-4-sulfonamide), with similar receptor binding and functional profile, additionally displayed remarkable antipsychotic properties in the MK-801-induced hyperlocomotor activity in mice.

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.

Synthesis and pharmacological evaluation of new arylpiperazines. 3-{4-[4-(3-chlorophenyl)-1-piperazinyl]butyl}-quinazolidin-4-one: A dual serotonin 5-HT1A/5-HT2A receptor ligand with an anxiolytic-like activity

On the basis of systematic studies on the structure-activity relationships in arylpiperazine group of serotonin ligands, 12 new derivatives containing quinazolidin-4(3H)-one (1-4), 2-phenyl-2,3-dihydrophthalazine-1,4-dione (5-8) or 1-phenyl-1,2-dihydropyridazine-3,6-dione (9-12) fragments were synthesized. The majority of the tested compounds (2, 4, 7, 8 and 10-12) showed a high affinity for 5-HT(1A) receptors (K(i)=11-54 nM) and two (1, 2) were found active at 5-HT(2A) sites (16 and 68 nM, respectively). All the new 5-HT(1A) ligands tested in vivo revealed an antagonistic activity at postsynaptic 5-HT(1A) receptors, and three of them behaved as agonists at presynaptic ones. Additionally, both the meta-chlorophenylpiperazine derivatives containing quinazolidin-4-one fragment showed features of 5-HT(2A) receptor antagonists. The dual 5-HT(1A)/5-HT(2A) receptor ligand (2) was further tested for its potential psychotropic activity. It showed a distinct anxiolytic-like activity in a conflict drinking test in rats and the observed effect was more potent in terms of the active dose, than that produced by diazepam (used as a reference drug).

1,2,3,4-tetrahydroisoquinoline derivatives: a new class of 5-HT1A receptor ligands.

Three series of new N-substituted 1,2,3,4-tetrahydroisoquinolines with 2-, 3-, and 4-membered alkyl chains (a, b, and c, respectively) were synthesized, and the effect of some structural modifications on their 5-HT1A receptor affinities and functional properties was discussed. It was found that the volume of the terminal amide substituent was a crucial parameter which determined 5-HT1A receptor affinities of the tested compounds, while the in vivo activity seemed to depend on both the R-volume and the length of a hydrocarbon chain. It was demonstrated that the most active ligands behaved like agonists or partial agonists at postsynaptic 5-HT1A receptors.

Structure-activity relationship studies of CNS agents. Part 29. N-Methylpiperazino-substituted derivatives of quinazoline, phthalazine and quinoline as novel α1, 5-HT1A and 5-HT2A receptor ligands

Summary New N -methylpiperazino-substituted quinazolines 8 and 9 , phthalazine 13 , and quinoline 19 have been synthesized. The receptor binding profiles (α 1 , 5-HT 1A , 5-HT 2A ) of these compounds and their analogs ( 7–22 ) have been determined. It has been demonstrated that orientation of a local dipole moment of the heteroaromatic ring system affects both the α 1 and 5-HT 2A affinity of the investigated class of ligands. Distortion of the coplanar unfused heteroaromatic ring system results in a decreased 5-HT 2A affinity. 4-(4-Methylpiperazino)-2-(2-thienyl)quinoline 18 is the most active and selective α 1 ligand ( K i = 4.9 nM) with a much lower affinity for 5-HT 1A ( K i = 3420 nM) and 5-HT 2A ( K i = 211 nM) receptors.

Structure-activity relationship studies of CNS agents-XVII. Spiro[piperidine-4′,1-(1,2,3,4-tetrahydro-β-carboline)] as a probe defining the extended topographic model of 5-HT1A receptors

Abstract Spiro[piperidine-4′,1-(1,2,3,4-tetrahydro-β-carboline)] ( 10 ), its derivatives 11–15 and its analogs 16 and 17 were examined as ligands of serotonin 5-HT 1A receptors. It was shown that compounds 12 and 14 had essentially the same 5-HT 1A affinity as 1-phenylpiperazine and its rigid analog 7 , whereas there were substantial differences in the steric arrangement of their crucial pharmacophores, i.e. aromatic and protonation centers. On the basis of the existing models and using the (+)-LSD structure as a template, a new, extended three-point topographic model of 5-HT 1A receptors has been proposed.

Novel 1,4‐Benzoxazin‐3(4H)‐one, 1,2‐Benzoxazolin‐3‐one and 1,3‐Benzoxazolin‐2,4‐dione Arylpiperazine Derivatives with Different 5‐HT1A and Antagonistic 5‐HT2A Activities

New 1‐arylpiperazine (series d—f) and 1,2,3,4‐tetrahydroisoquinoline (series g) derivatives of 1,4‐benzoxazin‐3(4H)‐one 1, 1,2‐benzoxazolin‐ 3‐one 2, and 1,3‐benzoxazolin‐2,4‐dione 3 with an n‐butyl chain were synthesized in order to explore the effect of spacer elongation on their binding affinity and in vivo functional activity at 5‐HT1A and 5‐HT2A receptors in comparison with trimethylene analogues (a, b c). 5‐HT1A receptor binding constants of derivatives 1d—g, 2d—f, and 3d—f were very high (Ki = 1.25—54 nM), and 5‐HT2A affinities were maintained at a similar, high level (Ki = 27—85 nM) for series d and e, and moderate (Ki = 246—495 nM) for series f. In respect of a spacer, the obtained results showed either no effect or a slight increase in the 5‐HT1A/5‐HT2A affinity in case of derivatives of 1 and 2, respectively. A striking effect was observed for derivatives 3d and 3f, whose 5‐HT1A affinity was reinforced by two orders of magnitude with a simultaneous decrease in 5‐HT2A binding constants in comparison with trimethylene analogues. As shown by X‐ray crystallography, this phenomenon may be attributed to the position of non‐carbonyl oxygen atom in the amide moiety. In vivo studies demonstrated that compounds 1e—g, 2d—f, and 3f behaved like typical postsynaptic 5‐HT1A receptor antagonists, whereas 3d and 3e might be qualified as their potential partial agonists. Moreover, 1e, 2e, and 3e demonstrated 5‐HT2A receptor antagonistic properties. Of the tested compounds, two derivatives showed some very outstanding properties: 3e may be regarded as a potential anxiolytic and/or antidepressant agent, while 3f as a new potent 5‐HT1A antagonist.

Acute and repeated treatment with the 5-HT7 receptor antagonist SB 269970 induces functional desensitization of 5-HT7 receptors in rat hippocampus

BACKGROUND SB 269970, a 5-HT(7) receptor antagonist may produce a faster antidepressant-like effect in animal models, than do antidepressant drugs, e.g., imipramine. The present work was aimed at examining the effect of single and repeated (14 days) administration of SB 269970 on the 5-HT(7) receptor in the hippocampus. METHODS The reactivity of 5-HT(7) receptors was determined using 5-carboxamidotryptamine (5-CT), which increased the bursting frequency of spontaneous epileptiform activity in hippocampal slices. Additionally, the effects of SB 269970 administration on the affinity and density of 5-HT(7) receptors were investigated using [(3)H]-SB 269970 and the influence of SB 269970 and imipramine on mRNA expression levels of Gα(s) and Gα(12) mRNA were studied using RT-qPCR. RESULTS Acute and repeated treatment with SB 269970 led to attenuation of the excitatory effects of activation of 5-HT(7) receptors. Neither single nor repeated administration of SB 269970 changed the mean affinity of 5-HT(7) receptors for [(3)H]-SB 269970. Repeated, but not single, administration of SB 269970 decreased the maximum density of [(3)H]-SB 269970 binding sites. While administration of imipramine did not change the expression of mRNAs for Gα(s) and Gα(12) proteins after both single and repeated administration of SB 269970, a reduction in Gα(s) and Gα(12) mRNA expression levels was evident. CONCLUSIONS These findings indicate that even single administration of SB269970 induces functional desensitization of the 5-HT(7) receptor system, which precedes changes in the receptor density. This mechanism may be responsible for the rapid antidepressant-like effect of the 5-HT(7) antagonist in animal models.

4-(3-furyl)-2-(4-methylpiperazino)pyrimidines: Potent 5-HT2A receptor antagonists

Abstract The title pyrimidines 7–12 are potent 5-HT2A receptor ligands with fairly strong behavioral antagonistic activity. A comparison of the structural and binding properties within the entire group of these and other pyrimidines demonstrates two different modes of the bioactive complex formation.