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Synthesis of several substituted phenylpiperazines behaving as mixed D2/5HT(1A) ligands

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1997
Authors
Dukić, Slađana
Kostić Rajačić, Slađana
Dragović, D
Šoškić, Vukić
Joksimović, J
Article (Published version)
,
J. Pharm. Pharmacol.
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Abstract
Twenty-two different compounds have been synthesized with the aim of creating new, mixed D2/5HT(1A) ligands. For this purpose l-substituted phenylpiperazines attached by the N-4 nitrogen to dopaminergic pharmacophores of the 2-(5-benzimidazole)ethyl-, 2-(5-benztriazole)ethyl-, 2-[5-(benzimidazole-2thione)]ethyl- and 2-[6-(1,4-dihydroquinoxaline-2,3-dione)]ethyl-type were selected according to known structure affinity requirements of l-arylpiperazines. All the new compounds were evaluated for in-vitro binding affinity at the dopamine (D1 and D2) and 5-HT(1A) receptors. Synaptosomal membranes prepared from fresh bovine caudate nuclei and hippocampi were used as a source of dopamine and 5-hydroxytryptamine receptors, respectively. [3H]SCH 23390 (D1 selective), [3H]spiperone (D2 selective) and 8-OH-[3H]DPAT (5-HT(1A) selective) were employed as the radio-ligands. None of the compounds expressed affinity for binding at D1 dopamine receptors. Compounds 3b and 4b were inactive 8-OH-[3H]DPAT c...ompetitors whereas 1b, 2b and 4b were inactive in the [3H] spiperone-binding assay. The other compounds tested showed fair (1c, 1e, 1f, 2c, 2f, 3b, 3c and 4c) to high (1a, 1d, 2a, 1d, 3a, 3d-3f, 4a, and 4d) affinity in the [3H]spiperone-binding assay, the most potent representative being 4-[2-(5-benzimidazole-2-thione)ethyl]1-(2-methoxyphenyl)piperazine, 3a (K(i)=1.7 nM). In the 8-OH-[3H]DPAT-displacement assay compounds 1b, 1d, 1f, 2b, 2f and 3f behaved as moderate competitors and 1a, 1c, 1e, 2a, 2c, 2d, 3a, 3c-3e, 4a, 4c, 4d and 4f as rather strong competitors; 4-[2-(5-benztriazole)ethyl]-1-(2-methoxyphenyl)piperazine, 2a had the highest binding affinity at the 5-HT(1A) receptors (K(i) = 2.6 nM). Because many antipsychotic and anxiolytic agents behave as mixed dopaminergic and serotonergic ligands, the high affinity of several of these new ligands for binding at both D2 and 5-HT(1A) receptors make them promising candidates deserving further pharmacological evaluation as antipsychotic or anxiolytic pharmaceuticals.

Keywords:
binding affinity
Source:
Journal of Pharmacy and Pharmacology, 1997, 49, 10, 1036-1041
Publisher:
  • Blackwell Publishing Ltd
Funding / projects:
  • Ministry of Science and Technology of Serbia

DOI: 10.1111/j.2042-7158.1997.tb06037.x

ISSN: 0022-3573

PubMed: 9364416

WoS: A1997YD31400018

Scopus: 2-s2.0-0030709249
[ Google Scholar ]
16
15
URI
https://cer.ihtm.bg.ac.rs/handle/123456789/2831
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  • Radovi istraživača / Researchers' publications
Institution/Community
IHTM
TY  - JOUR
AU  - Dukić, Slađana
AU  - Kostić Rajačić, Slađana
AU  - Dragović, D
AU  - Šoškić, Vukić
AU  - Joksimović, J
PY  - 1997
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/2831
AB  - Twenty-two different compounds have been synthesized with the aim of creating new, mixed D2/5HT(1A) ligands. For this purpose l-substituted phenylpiperazines attached by the N-4 nitrogen to dopaminergic pharmacophores of the 2-(5-benzimidazole)ethyl-, 2-(5-benztriazole)ethyl-, 2-[5-(benzimidazole-2thione)]ethyl- and 2-[6-(1,4-dihydroquinoxaline-2,3-dione)]ethyl-type were selected according to known structure affinity requirements of l-arylpiperazines. All the new compounds were evaluated for in-vitro binding affinity at the dopamine (D1 and D2) and 5-HT(1A) receptors. Synaptosomal membranes prepared from fresh bovine caudate nuclei and hippocampi were used as a source of dopamine and 5-hydroxytryptamine receptors, respectively. [3H]SCH 23390 (D1 selective), [3H]spiperone (D2 selective) and 8-OH-[3H]DPAT (5-HT(1A) selective) were employed as the radio-ligands. None of the compounds expressed affinity for binding at D1 dopamine receptors. Compounds 3b and 4b were inactive 8-OH-[3H]DPAT competitors whereas 1b, 2b and 4b were inactive in the [3H] spiperone-binding assay. The other compounds tested showed fair (1c, 1e, 1f, 2c, 2f, 3b, 3c and 4c) to high (1a, 1d, 2a, 1d, 3a, 3d-3f, 4a, and 4d) affinity in the [3H]spiperone-binding assay, the most potent representative being 4-[2-(5-benzimidazole-2-thione)ethyl]1-(2-methoxyphenyl)piperazine, 3a (K(i)=1.7 nM). In the 8-OH-[3H]DPAT-displacement assay compounds 1b, 1d, 1f, 2b, 2f and 3f behaved as moderate competitors and 1a, 1c, 1e, 2a, 2c, 2d, 3a, 3c-3e, 4a, 4c, 4d and 4f as rather strong competitors; 4-[2-(5-benztriazole)ethyl]-1-(2-methoxyphenyl)piperazine, 2a had the highest binding affinity at the 5-HT(1A) receptors (K(i) = 2.6 nM). Because many antipsychotic and anxiolytic agents behave as mixed dopaminergic and serotonergic ligands, the high affinity of several of these new ligands for binding at both D2 and 5-HT(1A) receptors make them promising candidates deserving further pharmacological evaluation as antipsychotic or anxiolytic pharmaceuticals.
PB  - Blackwell Publishing Ltd
T2  - Journal of Pharmacy and Pharmacology
T1  - Synthesis of several substituted phenylpiperazines behaving as mixed D2/5HT(1A) ligands
VL  - 49
IS  - 10
SP  - 1036
EP  - 1041
DO  - 10.1111/j.2042-7158.1997.tb06037.x
ER  - 
@article{
author = "Dukić, Slađana and Kostić Rajačić, Slađana and Dragović, D and Šoškić, Vukić and Joksimović, J",
year = "1997",
abstract = "Twenty-two different compounds have been synthesized with the aim of creating new, mixed D2/5HT(1A) ligands. For this purpose l-substituted phenylpiperazines attached by the N-4 nitrogen to dopaminergic pharmacophores of the 2-(5-benzimidazole)ethyl-, 2-(5-benztriazole)ethyl-, 2-[5-(benzimidazole-2thione)]ethyl- and 2-[6-(1,4-dihydroquinoxaline-2,3-dione)]ethyl-type were selected according to known structure affinity requirements of l-arylpiperazines. All the new compounds were evaluated for in-vitro binding affinity at the dopamine (D1 and D2) and 5-HT(1A) receptors. Synaptosomal membranes prepared from fresh bovine caudate nuclei and hippocampi were used as a source of dopamine and 5-hydroxytryptamine receptors, respectively. [3H]SCH 23390 (D1 selective), [3H]spiperone (D2 selective) and 8-OH-[3H]DPAT (5-HT(1A) selective) were employed as the radio-ligands. None of the compounds expressed affinity for binding at D1 dopamine receptors. Compounds 3b and 4b were inactive 8-OH-[3H]DPAT competitors whereas 1b, 2b and 4b were inactive in the [3H] spiperone-binding assay. The other compounds tested showed fair (1c, 1e, 1f, 2c, 2f, 3b, 3c and 4c) to high (1a, 1d, 2a, 1d, 3a, 3d-3f, 4a, and 4d) affinity in the [3H]spiperone-binding assay, the most potent representative being 4-[2-(5-benzimidazole-2-thione)ethyl]1-(2-methoxyphenyl)piperazine, 3a (K(i)=1.7 nM). In the 8-OH-[3H]DPAT-displacement assay compounds 1b, 1d, 1f, 2b, 2f and 3f behaved as moderate competitors and 1a, 1c, 1e, 2a, 2c, 2d, 3a, 3c-3e, 4a, 4c, 4d and 4f as rather strong competitors; 4-[2-(5-benztriazole)ethyl]-1-(2-methoxyphenyl)piperazine, 2a had the highest binding affinity at the 5-HT(1A) receptors (K(i) = 2.6 nM). Because many antipsychotic and anxiolytic agents behave as mixed dopaminergic and serotonergic ligands, the high affinity of several of these new ligands for binding at both D2 and 5-HT(1A) receptors make them promising candidates deserving further pharmacological evaluation as antipsychotic or anxiolytic pharmaceuticals.",
publisher = "Blackwell Publishing Ltd",
journal = "Journal of Pharmacy and Pharmacology",
title = "Synthesis of several substituted phenylpiperazines behaving as mixed D2/5HT(1A) ligands",
volume = "49",
number = "10",
pages = "1036-1041",
doi = "10.1111/j.2042-7158.1997.tb06037.x"
}
Dukić, S., Kostić Rajačić, S., Dragović, D., Šoškić, V.,& Joksimović, J.. (1997). Synthesis of several substituted phenylpiperazines behaving as mixed D2/5HT(1A) ligands. in Journal of Pharmacy and Pharmacology
Blackwell Publishing Ltd., 49(10), 1036-1041.
https://doi.org/10.1111/j.2042-7158.1997.tb06037.x
Dukić S, Kostić Rajačić S, Dragović D, Šoškić V, Joksimović J. Synthesis of several substituted phenylpiperazines behaving as mixed D2/5HT(1A) ligands. in Journal of Pharmacy and Pharmacology. 1997;49(10):1036-1041.
doi:10.1111/j.2042-7158.1997.tb06037.x .
Dukić, Slađana, Kostić Rajačić, Slađana, Dragović, D, Šoškić, Vukić, Joksimović, J, "Synthesis of several substituted phenylpiperazines behaving as mixed D2/5HT(1A) ligands" in Journal of Pharmacy and Pharmacology, 49, no. 10 (1997):1036-1041,
https://doi.org/10.1111/j.2042-7158.1997.tb06037.x . .

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