The impact of spacer structure on 5-HT7 and 5-HT1A receptor affinity in the group of long-chain arylpiperazine ligands (original) (raw)
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Archiv der Pharmazie, 2013
A series of new long-chain arylpiperazine (LCAP) derivatives with flexible and partly constrained alkyl linker were synthesized and investigated in vitro as potential serotonin 5-HT 1A and 5-HT 7 receptor ligands. The compounds were prepared by a two-step procedure using naphthalimide and 2H-1,3benzoxazine-2,4(3H)-dione as imides, and 1-(2-methoxyphenyl)piperazine (o-OMe-PhP) and 1,2,3,4tetrahydroisoquinoline (THIQ) as amine pharmacophores. Modifications of the spacer structure included introduction of flexible penta-and hexamethylene chains as well as partly constrained m-and p-xylyl moieties. In general, the new compounds were more active at the 5-HT 1A than at the 5-HT 7 receptor, and the o-OMe-PhP derivatives displayed higher affinities than their respective THIQ analogs. The spacer modifications had little effect on the observed in vitro activities. Within the o-OMe-PhP series, except for a small binding reduction for ligands containing the m-xylyl moiety, there was no substantial change in the compounds' potency at both receptors, while for the THIQ derivatives a clear structure-activity relationship was visible only for the interaction of the compounds with the 5-HT 7 receptor, which strongly favored flexible analogs.
…, 2011
The synthesis and evaluation as 5-HT 1A and 5-HT 7 serotonin receptor ligands of the two sets of O-substituted hydroxybenzamides, structurally related to 2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]pro-poxy}benzamide (1), (K i 5-HT 1A ¼ 21 nM, 5-HT 7 ¼ 234 nM) are reported. To affect the affinity for 5-HT 1A and 5-HT 7 receptors, an amide moiety (2-6) and a hydrocarbon chain length (7-10) were modified. The serotonergic activity of compounds 2-10 was generally higher in the case of 5-HT 1A receptors compared with 5-HT 7 ones; the most active 5-HT 1A ligands being meta-isomer 2 (K i ¼ 7 nM) and both analogs of 1 with the longest spacer, i.e., penta-and hexa-methylene derivatives 9 and 10 (K i ¼ 4 and 3 nM, respectively). The observed biological properties of compounds 1-10 were elucidated using molecular modeling procedures. J. Heterocyclic Chem., 48, 192 (2011).
Journal of Heterocyclic Chemistry, 2011
The synthesis and evaluation as 5-HT 1A and 5-HT 7 serotonin receptor ligands of the two sets of O-substituted hydroxybenzamides, structurally related to 2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]pro-poxy}benzamide (1), (K i 5-HT 1A ¼ 21 nM, 5-HT 7 ¼ 234 nM) are reported. To affect the affinity for 5-HT 1A and 5-HT 7 receptors, an amide moiety (2-6) and a hydrocarbon chain length (7-10) were modified. The serotonergic activity of compounds 2-10 was generally higher in the case of 5-HT 1A receptors compared with 5-HT 7 ones; the most active 5-HT 1A ligands being meta-isomer 2 (K i ¼ 7 nM) and both analogs of 1 with the longest spacer, i.e., penta-and hexa-methylene derivatives 9 and 10 (K i ¼ 4 and 3 nM, respectively). The observed biological properties of compounds 1-10 were elucidated using molecular modeling procedures. J. Heterocyclic Chem., 48, 192 (2011).
Towards the development of 5-HT7 ligands combining serotonin-like and arylpiperazine moieties
European Journal of Medicinal Chemistry, 2014
Many known 5-HT 7 ligands contain either a serotonin-like or an arylpiperazine structure that, in published SAR studies, are generally supposed to bind the same receptor pocket. Conversely, we explored the hypothesis that two such moieties can co-exist in the same ligand, binding to different pockets. We thus designed and synthesized a set of compounds including both a 5-hydroxyindol-3-ylethyl and a 1arylpiperazine moieties connected by a short linker. The compounds were tested for their affinity for human 5-HT 7 serotonin receptor. We further prepared a novel series of 5-HT 7 ligands, where the 5hydroxyindol-3-ylethyl moiety was bioisosterically replaced by a 3-hydroxyanilinoalkyl one. Among the newly synthesized compounds, potent ligands at the 5-HT 7 receptor, behaving as antagonists in functional tests, were identified, even if they showed limited subtype selectivity. Docking studies within a model of the 5-HT 7 receptor showed that the binding site can actually accommodate both moieties, with the serotonin-like one in the putative orthosteric site and the arylpiperazine one occupying an accessory pocket. The present results demonstrate that it is possible to devise and develop new 5-HT 7 ligands merging two privileged structures in the same molecule.
1997
Confortnational analysis for 24 arylpiperazines in their neutral and NJ-protonated forms has been performed in the AM1 framework. Both these derivatives and eight reference compounds considered in this study are ligands of the 5-HTIA serotoninergic receptor. Quantum chemical reactivity indices, solvation free energies (AMSOL 5.0) and molecular modelling derived ad hoc size and shape descriptors have been computed and correlated with the literature S-HT IA binding affinity data values. The quantitative size-shape affinity relationships obtained confirm the validity and versatility of the ad hoc descriptors employed. A different role has been postulated for the neutral and protonated forms of the arylpiperazines considered in the molecular recognition process of the 5-HTIA receptor binding site. 0 1997 Elsevier Science B.V.
Structure and Serotonin 5-HT2C Receptor Activity of ortho- and meta-Substituted Phenylpiperazines
Acta Crystallographica Section B Structural Science, 1997
The structural characteristics of ortho- and meta-substituted phenylpiperazines have been investigated in order to understand their actions at the serotonin 5-HT2c receptor. The crystal structures of the 4-methylated analogues of two phenylpiperazines that are already known as 5-HT2c ligands, 1-(1-naphthyl)-4-methylpiperazine (1NMP) and 1-[(3-trifluoromethyl)phenyl]-4-methylpiperazine (TFMPMP), and those of two novel 5-HT2c ligands, 1-(2-methoxyphenyl)piperazine (oMPP) and 1-(3-methoxyphenyl)piperazine (mMPP), are determined. Molecular mechanics calculations are performed to calculate the energy profiles of six phenylpiperazines for rotation about the central phenyl–nitrogen bond. The activities of several phenylpiperazines, in combination with their crystal structures and conformational characteristics, lead to the hypothesis that the conformation for which the piperazine ring and the phenyl ring are approximately co-planar should be the 5-HT2c receptor `activating' conformatio...
Journal of Molecular Structure: THEOCHEM, 1997
Confortnational analysis for 24 arylpiperazines in their neutral and NJ-protonated forms has been performed in the AM1 framework. Both these derivatives and eight reference compounds considered in this study are ligands of the 5-HTIA serotoninergic receptor. Quantum chemical reactivity indices, solvation free energies (AMSOL 5.0) and molecular modelling derived ad hoc size and shape descriptors have been computed and correlated with the literature S-HT IA binding affinity data values. The quantitative size-shape affinity relationships obtained confirm the validity and versatility of the ad hoc descriptors employed. A different role has been postulated for the neutral and protonated forms of the arylpiperazines considered in the molecular recognition process of the 5-HTIA receptor binding site. 0 1997 Elsevier Science B.V.
Journal of Combinatorial Chemistry, 2004
An efficient solid-supported method for the synthesis of a new class of arylpiperazine derivatives containing amino acid residues has been developed. A 72-membered library was synthesized on SynPhase Lanterns functionalized by a BAL linker. A one-pot cleavage/cyclization step of aspartic and glutamic acid derivatives yielded succinimide-and pyroglutamyl-containing ligands (chemsets 9 and 10). The library representatives under study showed different levels of affinity for 5-HT 1A and 5-HT 2A receptors (estimated K i) 24-4000 and 1-2130 nM, respectively). Several dual 5-HT 1A /5-HT 2A ligands were found, of which two (9{3,3} and 9{3,5}) displayed high 5-HT 2A affinity comparable to that of the reference drug ritanserin. A set of individual fragment contributions for the prediction of 5-HT 1A and 5-HT 2A affinity of all the library members were defined on the basis of the Free-Wilson analysis of 26 compounds. An alkylarylpiperazine fragment had essentially the same impact on the affinity for both receptors, whereas different terminal amide fragments were preferred by 5-HT 1A (chemset 17, R 2) adamantyl) and 5-HT 2A (chemset 9, R 2) norborn-2-ylmethyl) binding sites.