[3H]prazosin binding to central nervous system regions of male and female rats

A series of new arylpiperazine derivatives 2, which are devoid of the terminal amide fragment present in related 5-HT1A ligands, was prepared and evaluated for affinity at 5-HT1A and alpha 1 receptors. All the compounds 2 demonstrated high affinity for the 5-HT1A receptor and moderate affinity for alpha 1 receptor binding sites. Structure-activity relationship (SAR) studies suggest that there is influence of electronic factors on the no-pharmacophoric part of the alpha 1 receptor site. However there is no influence of electronic interactions on the stabilization of the 5-HT1A receptor-ligand complex.

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“…α 1 Adrenoceptor. The radioligand receptor binding studies were performed according to a previously described procedure …”

Section: Methodsmentioning

confidence: 99%

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 3. 2-[ω-(4-Arylpiperazin-1-yl)alkyl]perhydropyrrolo- [1,2-c]imidazoles and -perhydroimidazo[1,5-a]pyridines: Study of the Influence of the Terminal Amide Fragment on 5-HT_1A Affinity/Selectivity

et al. 1997

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“…α 1 Adrenoceptor. The radioligand receptor binding studies were performed according to a previously described procedure . The cerebral cortex was homogenized in 20 vol of ice-cold buffer (50 mM Tris-HCl, 10 mM MgCl 2 , pH 7.7 at 25 °C) and centrifuged at 30000 g for 15 min.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 1. 2-[[4-(o-Methoxyphenyl)piperazin-1-yl]methyl]-1,3- dioxoperhydroimidazo[1,5-a]pyridine: A Selective 5-HT_1A Receptor Agonist

et al. 1996

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A series of new bicyclohydantoin-arylpiperazines was prepared and evaluated for affinity at 5-HT1A, alpha 1, and D2 receptors. Most of the compounds showed very low affinity for D2 receptors, and most of them demonstrated moderate to high affinity for 5-HT1A and alpha 1 receptor binding sites. SAR observations indicated that the length of the alkyl chain between the arylpiperazine and the hydantoin moiety is of great importance for 5-HT1A/alpha 1 affinity and selectivity, n = 1 being the optimal value. Compound 1h, 2-[[4-(o-methoxyphenyl)piperazin-1-yl] methyl]-1,3-dioxoperhydroimidazo [1,5-alpha]pyridine, bound at 5-HT1A sites with nanomolar affinity (Ki = 31.7 nM) and high selectivity over alpha 1, D2, and 5-HT2A receptors (Ki > 1000, > 10 000, and > 1000 nM, respectively). Preliminary studies showed that this agent is probably functioning as a partial to full 5-HT1A agonist, and it displayed anxiolytic activity on the social interaction test in mice.

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“…The radioligand receptor binding studies were performed according to a previously described procedure. 26 The cerebral cortex was homogenized in 20 volumes of ice-cold buffer (50 mM Tris-HCl, 10 mM MgCl2, pH 7.4 at 25 °C) and centrifuged at 30000g for 15 min. Pellets were washed twice by resuspension and centrifugation.…”

Section: -[3-[4-(o-butoxyphenyl)piperazin-1-yl]propyl]-13-dioxoperhyd...mentioning

confidence: 99%

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 5. Study of the Physicochemical Influence of the Pharmacophore on 5-HT_1A/α₁-Adrenergic Receptor Affinity: Synthesis of a New Derivative with Mixed 5-HT_1A/D₂ Antagonist Properties

et al. 2000

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In this paper we have designed and synthesized a test series of 32 amide arylpiperazine derivatives VI in order to gain insight into the physicochemical influence of the pharmacophores of 5-HT(1A) and alpha(1)-adrenergic receptors. The training set was designed applying a fractional factorial design using six physicochemical descriptors. The amide moiety is a bicyclohydantoin or a diketopiperazine (X = -(CH(2))(3)-, -(CH(2))(4)-; m = 0, 1), the spacer length is 3 or 4 methylene units, which are the optimum values for both receptors, and the aromatic substituent R occupies the ortho- or meta-position and has been selected from a database of 387 substituents using the EDISFAR program. The 5-HT(1A) and alpha(1)-adrenergic receptor binding affinities of synthesized compounds VI (1-32) have been determined. This data set has been used to derive classical quantitative structure-activity relationships (QSAR) and neural networks models for both receptors (following paper). A comparison of these models gives information for the design of the new ligand EF-7412 (46) (5-HT(1A): K(i) = 27 nM; alpha(1): K(i) > 1000 nM). This derivative displays affinity for the dopamine D(2) receptor (K(i) = 22 nM) and is selective versus all other receptors examined (5-HT(2A), 5-HT(3), 5-HT(4) and Bz; K(i) > 1000 nM). EF-7412 (46) acts as an antagonist in vivo in pre- and postsynaptic 5-HT(1A) receptor sites and as an antagonist in the dopamine D(2) receptor. Thus, EF-7412 (46) is a derivative with mixed 5-HT(1A)/D(2) antagonist properties and this derivative could be useful as a pharmacological tool.

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[3H]prazosin binding to central nervous system regions of male and female rats

Cited by 26 publications

References 15 publications

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 3. 2-[ω-(4-Arylpiperazin-1-yl)alkyl]perhydropyrrolo- [1,2-c]imidazoles and -perhydroimidazo[1,5-a]pyridines: Study of the Influence of the Terminal Amide Fragment on 5-HT_1A Affinity/Selectivity

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 3. 2-[ω-(4-Arylpiperazin-1-yl)alkyl]perhydropyrrolo- [1,2-c]imidazoles and -perhydroimidazo[1,5-a]pyridines: Study of the Influence of the Terminal Amide Fragment on 5-HT_1A Affinity/Selectivity

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 1. 2-[[4-(o-Methoxyphenyl)piperazin-1-yl]methyl]-1,3- dioxoperhydroimidazo[1,5-a]pyridine: A Selective 5-HT_1A Receptor Agonist

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 5. Study of the Physicochemical Influence of the Pharmacophore on 5-HT_1A/α₁-Adrenergic Receptor Affinity: Synthesis of a New Derivative with Mixed 5-HT_1A/D₂ Antagonist Properties

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[3H]prazosin binding to central nervous system regions of male and female rats

Cited by 26 publications

References 15 publications

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 3. 2-[ω-(4-Arylpiperazin-1-yl)alkyl]perhydropyrrolo- [1,2-c]imidazoles and -perhydroimidazo[1,5-a]pyridines: Study of the Influence of the Terminal Amide Fragment on 5-HT1A Affinity/Selectivity

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 3. 2-[ω-(4-Arylpiperazin-1-yl)alkyl]perhydropyrrolo- [1,2-c]imidazoles and -perhydroimidazo[1,5-a]pyridines: Study of the Influence of the Terminal Amide Fragment on 5-HT1A Affinity/Selectivity

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 1. 2-[[4-(o-Methoxyphenyl)piperazin-1-yl]methyl]-1,3- dioxoperhydroimidazo[1,5-a]pyridine: A Selective 5-HT1A Receptor Agonist

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 5. Study of the Physicochemical Influence of the Pharmacophore on 5-HT1A/α1-Adrenergic Receptor Affinity: Synthesis of a New Derivative with Mixed 5-HT1A/D2 Antagonist Properties

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Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 3. 2-[ω-(4-Arylpiperazin-1-yl)alkyl]perhydropyrrolo- [1,2-c]imidazoles and -perhydroimidazo[1,5-a]pyridines: Study of the Influence of the Terminal Amide Fragment on 5-HT_1A Affinity/Selectivity

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 3. 2-[ω-(4-Arylpiperazin-1-yl)alkyl]perhydropyrrolo- [1,2-c]imidazoles and -perhydroimidazo[1,5-a]pyridines: Study of the Influence of the Terminal Amide Fragment on 5-HT_1A Affinity/Selectivity

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 1. 2-[[4-(o-Methoxyphenyl)piperazin-1-yl]methyl]-1,3- dioxoperhydroimidazo[1,5-a]pyridine: A Selective 5-HT_1A Receptor Agonist

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 5. Study of the Physicochemical Influence of the Pharmacophore on 5-HT_1A/α₁-Adrenergic Receptor Affinity: Synthesis of a New Derivative with Mixed 5-HT_1A/D₂ Antagonist Properties