Sijka Charakchieva-Minol

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.

Synthesis, 5-HT1A and 5-HT2A receptor affinity of new 1-phenylpiperazinylpropyl derivatives of purine-2,6- and pyrrolidine-2,5-diones

Two series of 1-phenylpiperazinylpropyl derivatives 10, 11, 16, 17 and 19-24, structurally related to previously described 5-HT1A or 5-HT2A ligands 4 and 1, respectively, were synthesized and their binding properties were determined. Structural modifications which involved 1,3-diazepine ring opening in 4 (compounds 10, 11, 15, 16) and replacement of spiroalkyl moiety in 1 by aryl substituent (19-24) did not improve binding affinity and selectivity of the tested compounds. The results showed, however, that the diazepine ring present in 4 or spiroalkyl ring in 1 are important for high 5-HT1A or 5-HT2A binding affinity and selectivity of these compounds.

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).

A new putative 5-HT1A receptor antagonist of the 1-arylpiperazine class of ligands

Summary 5-HT 1A and 5-HT 2A receptor affinities of several ω-alkyl-1-arylpiperazines containing a terminal pyrimidopurine or 1,3-diazepinopurine ring system are reported. Several behavioral models demonstrated that l,3-dimethyl-9-[3-(4-phenyl-1-piperazinyl) propyl]-2,4,8-trioxo-l,3,9-trihydropyrimidino[2,1- f ]purine 8 and its analogs 5 and 6 may be classified as 5-HT 1A postsynaptic antagonists, whereas 7, 9 and 10 are partial agonists of 5-HT 1A receptors.

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.

Biologically Active 1-Arylpiperazines. Synthesis of New N-(4- Aryl-1-piperazinyl)alkyl Derivatives of Quinazolidin-4(3H)-one, 2,3-Dihydrophthalazine-1,4-dione and 1,2-Dihydropyridazine- 3,6-dione as Potential Serotonin Receptor Ligands

The synthesis of a series of new n-propyl and n-butyl chain containing 1-aryl-piperazine derivatives of quinazolidin-4(3H)-one (7) 2-phenyl-2,3-dihydrophthalazine-1,4-dione (8) and 1-phenyl-1,2-dihydropyridazine-3,6-dione (9) as potential serotonin receptor ligands is described.

Benzolactam derivatives and their affinity for α1-and α2-Adrenoreceptors

A series of benzolactam derivatives has been evaluated for their affinity for α1 and α2‐adrenoreceptors. The influence of terminal amine and amide fragments on the affinity and selectivity has been investigated. It has been found that derivatives containg 1,2,3,4‐tetrahydroisoquinoline (THIQ) as the basic component can form potent α1 and/or α2 ligands, and that their α1/α2 selectivity depends on the benzolactam fragment.

Influence of the terminal amide fragment geometry in some 3-arylideneindolin-2(1H)-ones on their 5-HT1A/5-HT2A receptor activity

Several 1,4-disubstituted arylpiperazine derivatives of 3-arylideneindolin-2(1H)-one (Z and E isomers) were tested for their 5-HT1A and 5-HT2A receptor activity in vitro and in vivo. It was shown that introduction of 3-arylidene substituents to indolin-2(1H)-one moiety allowed to change the mixed 5-HT1A/5-HT2A receptor ligands to 5-HT2A ones with antagonistic in vivo activity.