Conformational restriction in novel NAN-190 and MP3022 analogs and their 5-HT(1A) receptor activity.

The newly synthesized analogs of NAN-190 containing m-Cl and m-CF(3) substituents in the arylpiperazine moiety and their conformationally restricted counterparts showed a very high 5-HT(1A )receptor affinity. In the LLR test, the flexible compounds 4a and 5a displayed features of a partial agonist and agonist, respectively. The conformational restriction in the tested structures caused alternations in the observed in vivo effects; compounds 4b and 5b were classified as an inactive agent and an antagonist of postsynaptic 5-HT(1A )receptors, respectively.

Synthesis and 5-HT1A/5-HT2A receptor activity of N-(4-arylpiperazin-1-yl)alkyl derivatives of 2-azaspiro([4.4]nonane and [4.5]decane-1,3-dione.

Two series of N-[(4-arylpiperazin-1-yl)-alkyl]-2-azaspiro[4.4]nonane (5-10) and [4.5]decane-1,3-dione (11-16) derivatives were synthesized and their serotonin 5-HT1A and 5-HT2A receptor affinities were determined.

Synthesis, anticonvulsant properties and 5-HT1A/5-HT2A receptor affinity of new N-[(4-arylpiperazin-1-yl)-propyl]-2-aza-spiro[4.4]nonane and [4.5]decane-1,3-dione derivatives.

A series of twenty new N-[(4-arylpiperazin-1-yl)-propyl]-2-aza-spiro[4.4]nonane- and [4.5]decane-1,3-dione derivatives were synthesized and their anticonvulsant activity was evaluated in maximal electroshock (MES) and sc pentertazole (sc PTZ) tests.

New 4-[omega-(diarylmethylamino)alkyl]- and 4-[omega-(diarylmethoxy)alkyl]-1-arylpiperazines as selective 5-HT1A/5-HT2A receptor ligands with differentiated in vivo activity.

Two series of novel 4-ethyl- or 4-propyl-1-arylpiperazines (5-12) with the 4,4'-disubstituted diphenylmethylamino (series a) or the diphenylmethoxy (series b) terminal fragment were synthesized and evaluated for their binding affinity at 5-HT1A and 5-HT2A receptors. The influence of the introduction of 4-methyl, 4-chloro or 4-fluoro substituents at both phenyl rings of that terminal moiety on in vitro and in vivo 5-HT1A receptor activity of those modified compounds was discussed. Compounds 5a, 6a, 9a-12a, 5b, 6b, 9b, 11b and 12b displayed high to fairly high affinity for 5-HT1A receptors (Ki = 2.

New arylpiperazine 5-HT(1A) receptor ligands containing the pyrimido[2,1-f]purine fragment: synthesis, in vitro, and in vivo pharmacological evaluation.

New 1H,3H-pyrimido[2,1-f]purine-2,4-dione derivatives of arylpiperazine (11-22) were prepared and evaluated in vitro for their affinity for 5-HT(1A), 5-HT(2A), alpha(1), and D(2) receptors. The tested compounds showed high affinity for 5-HT(1A) and alpha(1) receptors (K(i) = 1.1-87 and 10-62 nM, respectively) and moderate to low affinity for 5-HT(2A) (K(i) = 56-881 nM) and D(2) receptors (K(i) = 94-1245 nM).

Synthesis, in vitro and in vivo 5-HT1A/5-HT2A serotonin receptor activity of new hybrid 1,2,3,4-tetrahydro-gamma-carbolines with 1-(2-methoxyphenyl)piperazine moiety.

A series of 15 new 2-H- and 2-substituted 5-[omega-[4-(2-methoxyphenyl)-piperazinyl]-alkyl]-1,2,3,4-tetrahydro-gamma-carboline derivatives were prepared, and their affinity for 5-HT1A and 5-HT2A serotonin receptors was determined. Most of those hybrid compounds were found to bind with high affinity to 5-HT1A sites (Ki < 50 nM; 2d, 3a, 3b, 3d, 3e, 4b, 4d, 4e) and moreover two of them (4d, 4e) were mixed 5-HT1A/5-HT2A ligands. The results of a lower lip retraction test in rats indicated that the 2-acetyl derivative with a dimethylene spacer (2d) had features of a postsynaptic 5-HT1A receptor agonist, whereas its analogues with longer chains (3d and 4d) behaved like antagonists.

Novel 4-alkyl-1-arylpiperazines and 1,2,3,4-tetrahydroisoquinolines containing diphenylmethylamino or diphenylmethoxy fragment with differentiated 5-HT1A/5-HT2A/D2 receptor activity.

Two series of 4-alkyl-1-arylpiperazines (1-4) and 1,2,3,4-tetrahydroiso-quinolines (5, 6) with diphenylmethylamino (series a) or diphenylmethoxy (series b) fragment were synthesized in order to obtain potential ligands of 5-HT1A and/or 5-HT2A and dopamine D2 receptors. Four new arylpiperazines (1a, 3a, 1b, 3b) were found to demonstrate high 5-HT1A receptor affinity (Ki = 1.5-35 nM); among them, 3a exhibited satisfactory 5-HT2A receptor affinity (Ki = 74 nM).

Novel N-[omega-[4-(2-methoxyphenyl)piperazin-1-yl]-ethyl]pyrid-2(1H)-ones with diversified 5-HT1A receptor activity.

Novel omega-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl derivatives 1-6 containing 4-, 5- and/or 6-arylsubstituted pyrid-2(1H)-one moiety were synthesized. All the new compounds were examined in vitro to assess their 5-HT1A and 5-HT2A receptor affinities. Compounds 3 and 4 with a 5- or a 6-phenylsubstituted pyridone ring demonstrated high 5-HT1A receptor affinity (Ki = 17 and 38 nM, respectively) and were tested in behavioral functional models.

Modification of the structure of 4, 6-disubstituted 2-(4-alkyl-1-piperazinyl)pyridines: synthesis and their 5-HT2A receptor activity.

Structure-activity relationship studies of a series of novel 4, 6-disubstituted 2-(1-piperazinyl)pyridines were conducted to revise our model of serotonin 5-HT(2A) receptor antagonist. Target compounds were synthesized using the benzotriazole-assisted Katritzky method. The majority of those compounds were found to be selective 5-HT(2A)/5-HT(1A) receptor ligands, though less potent than their previously described pyrimidine counterparts.

Synthesis and pharmacological evaluation of new arylpiperazines. 3-[4-[4-(3-chlorophenyl)-1-piperazinyl]butyl]-quinazolidin-4-one - a dual serotonin 5-HT(1A)/5-HT(2A) 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.

Active conformation of some arylpiperazine postsynaptic 5-HT(1A) 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 influence of substitution at aromatic part of 1,2,3,4-tetrahydroisoquinoline on in vitro and in vivo 5-HT(1A)/5-HT(2A) 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.