Synthesis of several substituted phenylpiperazines behaving as mixed D2/5HT(1A) ligands
Само за регистроване кориснике
1997
Чланак у часопису (Објављена верзија)
,
J. Pharm. Pharmacol.
Метаподаци
Приказ свих података о документуАпстракт
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.
Кључне речи:
binding affinityИзвор:
Journal of Pharmacy and Pharmacology, 1997, 49, 10, 1036-1041Издавач:
- Blackwell Publishing Ltd
Финансирање / пројекти:
- 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
Институција/група
IHTMTY - 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 . .