The impact of spacer structure on 5-HT7 and 5-HT1A receptor affinity in the group of long-chain arylpiperazine ligands (original) (raw)
2004, Bioorganic & Medicinal Chemistry Letters
https://doi.org/10.1016/J.BMCL.2004.09.029
Sign up for access to the world's latest research
checkGet notified about relevant papers
checkSave papers to use in your research
checkJoin the discussion with peers
checkTrack your impact
Abstract
New cis-, trans-2-butene and 1,2-bismethylbenzene analogues of MM77 and NAN-190 (1-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-pyrrolidine-2,5-dione and isoindole-1,3-dione, respectively) were synthesized. The differences in their in vitro affinity for serotonin 5-HT 7 and 5-HT 1A receptors were explained using a conformational analysis. A bioactive conformation of those compounds for the 5-HT 7 receptor, different from that established for 5-HT 1A , was proposed.
Related papers
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.
European journal of medicinal chemistry, 2010
The 5-HT 1A and a 1-receptor binding affinities of the arylpiperazinylthioalkyl derivatives have been quantitatively expressed in terms of topological and molecular features. The analysis revealed that a lower value of atomic composition based index (AAC), higher values of structural information content (SIC3) and topological charge index (GGI9) would be beneficial to the 5-HT 1A receptor binding. For the a 1-receptor binding affinity the higher values of topological charge index (GGI9) and atomic Sanderson electronegativities weighted descriptor (GATS3e) and more number of hydrogen atoms attached to sp or sp 3 hybridized carbon atoms in a molecular structure (H-047) would be favorable. The derived significant models may further be used to synthesize new potential and selective compounds.
Bioorganic & Medicinal Chemistry Letters, 2013
Here we report the synthesis, pharmacological and pharmacokinetic evaluation of a pilot set of compounds structurally related to the potent and selective 5-HT 7 ligand LP-211. Among the studied compounds, N-pyridin-3-ylmethyl-3-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]ethoxy]propanamide (4b) showed high affinity for 5-HT 7 receptors (K i = 23.8 nM), selectivity over 5-HT 1A receptors (>50-fold), in vitro metabolic stability (82%) and weak interaction with P-glycoprotein (BA/AB = 3.3). Compound 4b was injected ip in mice to preliminarily evaluate its distribution between blood and brain.
Journal of The Serbian Chemical Society, 2006
Serotonin receptors (5-HTRs), especially the 5-HT 1A subtype, have been the subject of intensive research for the past decade, due to their function in human physiology. Several structurally different classes of ligands are known to bind to the 5-HT 1A receptor, but arylpiperazine derivatives are among the most important ligands. In the work, docking analyses were used to explain the binding affinities of a series of ligands with different N-1 substituent. All ligands had in common the arylpiperazine structure, while the N-1 substituent was modified to investigate the influence of ligand structure on its binding affinity. The shape and size, as well as the rigidity of the substituents were altered to investigate the possible effects on the formation of the receptor -ligand complex.
Journal of Medicinal Chemistry, 2005
New arylpiperazine derivatives were prepared to identify highly selective and potent ligands for the 5-hydroxytryptamine 1A (5-HT 1A) receptor as potential pharmacological tools in studies of central nervous system (CNS) disorders. The combination of structural elements (heterocyclic nucleus, oxyalkyl chain, and arylpiperazine) known to introduce 5-HT 1A receptor affinity and the proper selection of substituents led to compounds with higher receptor specificity and affinity. In binding studies, several molecules showed affinity in the nanomolar and subnanomolar ranges at 5-HT 1A and moderate to no affinity for other relevant receptors (5-HT 2A , 5-HT 2C , D 1 , D 2 , R 1 , and R 2). The 4-[3-[4-(o-methoxyphenyl)piperazin-1-yl]propoxy]-4-aza-tricyclo-[5.2.1.02,6]dec-8-ene-3,5-dione (3b), with K i) 0.021 nM, was the most active and selective derivative for the 5-HT 1A receptor with respect to other serotonin receptors, whereas the most selective derivative for dopaminergic and adrenergic receptors was a CF 3-substituted arylpiperazine (2e). As a general trend, compounds with a piperazinylpropoxy chain (3b-g) showed a preferential affinity for the 5-HT 1A receptor, suggesting that the alkyl chain length represents a critical structural feature in determining 5-HT 1A receptor affinity and selectivity, as confirmed by the molecular modeling invoked for explaining the differential binding affinities of the new arylpiperazines.
Forensic Sciences Research, 2018
A series of N,N-disubstituted piperazines were synthesized containing the structural elements of both methylenedioxybenzylpiperazine (MDBP) and trifluoromethylphenylpiperazine (TFMPP) in a single molecule. These six potential designer drug molecules having a regioisomeric relationship were compared in gas chromatography-mass spectrometry (GC-MS), gas chromatography-infrared spectroscopy and serotonin receptor affinity studies. These compounds were separated by capillary gas chromatography on an Rxi Ò -17Sil MS stationary phase film and the elution order appears to be determined by the position of aromatic ring substitution. The majority of electron ionization mass spectral fragment ions occur via processes initiated by one of the two nitrogen atoms of the piperazine ring. The major electron ionization mass spectrometry (EI-MS) fragment ions observed in all six of these regioisomeric substances occur at m/z = 364, 229, 163 and 135. The relative intensity of the various fragment ions is also equivalent in each of the six EI-MS spectra. The vapour phase infrared spectra provide a number of absorption bands to differentiate among the six individual compounds on this regioisomeric set. Thus, the mass spectra place these compounds into a single group and the vapour phase infrared spectra differentiate among the six regioisomeric possibilities. All of the TFMPP-MDBP regioisomers displayed significant binding to 5-HT 2B receptors and in contrast to 3-TFMPP, most of these TFMPP-MDBP isomers did not show significant binding at 5-HT 1 receptor subtypes. Only the 3-TFMPP-3,4-MDBP (Compound 5) isomer displayed affinity comparable to 3-TFMPP at 5-HT 1A receptors (K i = 188 nmol/L).
Bioorganic & Medicinal Chemistry Letters, 1998
In the present paper, we report the synthesis and the binding profile on %HT,,, ~1, and D, receptors of a new series of imide-arylpiperazines 3. The study of the length of the alkyl chain and the imide substructure allows us to suggest some important differences between the no-pharmacophoric sites of both S-HT,, and cr,-adrenergic receptors, which could be of great importance in order to design new selective ligands.
Loading Preview
Sorry, preview is currently unavailable. You can download the paper by clicking the button above.
References (22)
- References and notes
- Bard, J. A.; Zgombick, J.; Adham, N.; Vaysse, P.; Branchek, T. A.; Weinshank, R. L. J. Biol. Chem. 1993, 268, 23422.
- Lovenberg, T. W.; Baron, B. M.; de Lecea, L.; Miller, J. D.; Prosser, R. A.; Rea, M. A.; Foye, P. E.; Racke, M.; Slone, A. L.; Siegel, B. W.; Danielson, P. E.; Sutcliffe, J. G.; Erlander, M. G. Neuron 1993, 11, 449.
- Tsou, A. P.; Kosaka, A.; Bach, C.; Zuppan, P.; Yee, C.; Tom, L.; Alvarez, R.; Ramsey, S.; Bonhaus, D. W.; Stefanich, E.; Jakeman, L.; Eglen, R. M.; Chan, H. J. Neurochem. 1994, 63, 456.
- Lovell, P. J.; Bromidge, S. M.; Dabbs, S.; Duckworth, D. M.; Forbes, I. T.; Jennings, A. J.; King, F. D.; Middle- miss, D. N.; Rahman, S. K.; Saunders, D. V.; Collin, L. L.; Hagan, J. J.; Riley, G. J.; Thomas, D. R. J. Med. Chem. 2000, 43, 342.
- Forbes, I. T.; Douglas, S.; Gribble, A. D.; Ife, R. J.; Lightfoot, A. P.; Garner, A. E.; Riley, G. J.; Jeffrey, P.; Stevens, A. J.; Stean, T. O.; Thomas, D. R. Bioorg. Med. Chem. Lett. 2002, 12, 3341.
- Leopoldo, M. Curr. Med. Chem. 2004, 11, 629.
- Thomas, D. R.; Hagan, J. J. Curr. Drug Targets CNS. Neurol. Disord. 2004, 3, 81.
- Lopez-Rodriguez, M. L.; Porras, E.; Morcillo, M. J.; Benhamu, B.; Soto, L. J.; Lavandera, J. L.; Ramos, J. A.; Olivella, M.; Campillo, M.; Pardo, L. J. Med. Chem. 2003, 46, 5638.
- Perrone, R.; Berardi, F.; Colabufo, N. A.; Lacivita, E.; Leopoldo, M.; Tortorella, V. J. Med. Chem. 2003, 46, 646.
- Wilcox, R. E.; Ragan, J. E.; Pearlman, R. S.; Brusniak, M. Y.; Eglen, R. M.; Bonhaus, D. W.; Tenner, T. E., Jr.; Miller, J. D. J. Comput. Aided Mol. Des. 2001, 15, 883.
- Mokrosz, M. J.; Chojnacka-Wo ´jcik, E.; Tatarczyn ˜ska, E.; Kłodzin ˜ska, A.; Filip, M.; Boksa, J.; Charakchieva- Minol, S.; Mokrosz, J. L. Med. Chem. Res. 1994, 4, 161.
- Glennon, R. A.; Naiman, N. A.; Pierson, M. E.; Titeler, M.; Lyon, R. A.; Weisberg, E. Eur. J. Pharmacol. 1988, 154, 339.
- Paluchowska, M. H.; Bojarski, A. J.; Charakchieva- Minol, S.; Wesołowska, A. Eur. J. Med. Chem. 2002, 37, 273.
- Paluchowska, M. H.; Mokrosz, M. J.; Bojarski, A. J.; Wesołowska, A.; Borycz, J.; Charakchieva-Minol, S.; Chojnacka-Wo ´jcik, E. J. Med. Chem. 1999, 42, 4952.
- Aguirre, N.; Ballaz, S.; Lasheras, B.; Del Rio, J. Eur. J. Pharmacol. 1998, 346, 181.
- Bojarski, A. J.; Cegła, M. T.; Charakchieva-Minol, S.; Mokrosz, M. J.; Mac ´kowiak, M.; Mokrosz, J. L. Phar- mazie 1993, 48, 289.
- Norman, M. H.; Minick, D. J.; Rigdon, G. C. J. Med. Chem. 1996, 39, 149.
- Lopez-Rodriguez, M. L.; Morcillo, M. J.; Rovat, T. K.; Fernandez, E.; Vicente, B.; Sanz, A. M.; Hernandez, M.; Orensanz, L. J. Med. Chem. 1999, 42, 36.
- Perrone, R.; Berardi, F.; Colabufo, N. A.; Leopoldo, M.; Lacivita, E.; Tortorella, V.; Leonardi, A.; Poggesi, E.; Testa, R. J. Med. Chem. 2001, 44, 4431.
- Klamt, A.; Schu ¨u ¨rmann, G. J. Chem. Soc., Perkin Trans. 2 1993, 799.
- Figure 4. Superimposition of MM-77, 2 and 3 in the extended conformation on rigid cyclohexane derivative 5 (orthogonal view)--a bioactive LCAP conformation for the 5-HT 1A receptor (A). Superpo- sition of MM-77 and 3 on the global energy minimum conformation of
Related papers
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.
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).
…, 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.
Journal of Medicinal Chemistry, 1999
Novel 5-HT 3 receptor ligands were designed and synthesized with the aim of obtaining deeper insight into the molecular basis of the intrinsic efficacy of arylpiperazines interacting with the central 5-HT 3 receptor. The newly synthesized compounds and some previously published compounds belonging to the same class of heteroarylpiperazines were tested for their potential ability to displace [ 3 H]granisetron from rat cortical membranes. These 5-HT 3 receptor binding studies revealed subnanomolar affinity in several of the compounds under study. The most active ligands were quipazine derivatives bearing a phenyl group in the 4-position and various oxygenated alkyl side chains in the 3-position of the quinoline nucleus. Qualitative and theoretical quantitative structure-affinity relationship studies were carried out, and the interaction model for the 5-HT 3 ligands related to quipazine with their receptor, proposed in part 1 of the present work, was updated to incorporate the latest data. The potential 5-HT 3 agonist/antagonist activity of 12 selected compounds was assessed in vitro on the 5-HT 3 receptordependent [ 14 C]guanidinium uptake in NG 108-15 cells. Their intrinsic efficacy ranged from the 5-HT 3 full agonist properties of compounds 7a and 8h,i to those of partial agonists 10a,d and antagonists 8b,d,e, and 9c,d,h,i. The comparison between these functional data and those relative to the previously described compounds suggested that in this class of 5-HT 3 ligands the intrinsic efficacy is modulated in a rather subtle manner by the steric features of the heteroaryl moiety.
Journal of medicinal chemistry, 1996
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.
Bivalent Ligands for the Serotonin 5-HT 3 Receptor
ACS Medicinal Chemistry Letters, 2011
S erotonin 5-HT 3 receptor (5-HT 3 R) belongs to the family of the ligand-gated ion channels (LGICs) and shows a pentameric structure similar to that of nicotinic acetylcholine (nACh), glycine, and type A γ-aminobutyric acid (GABA A ) receptors. 1,2 By virtue of its multimeric architecture, 5-HT 3 R represents an intriguing example of intrinsically multivalent biological receptors. Initially, a single 5-HT 3 R subunit (5-HT 3A ) was cloned, and subsequently, other 5-HT 3 R subunits (5-HT 3B -5-HT 3E ) have been identified. 1,2 The 5-HT 3A cDNA forms functional homopentameric cell surface receptors, whereas 5-HT 3B was reported to form functional 5-HT 3 Rs when expressed together with 5-HT 3A but not when expressed alone. 1,2 The three-dimensional structure of 5-HT 3 R has not yet been determined at an atomic level, but a large amount of site-directed mutagenesis experiments have been performed to gather information about structure and function, 1À3 and the data obtained have been used in the building of 3D receptor homology models. The research activity performed by the pharmaceutical companies in the development of 5-HT 3 R antagonists has produced a large number of drug molecules showing remarkable efficacy in preventing acute chemotherapy-induced nausea and vomiting. Our interest in the development of 5-HT 3 R ligands started from the study of arylpiperazine derivatives related to quipazine (Scheme 1) and has since produced a considerable amount of information on the interaction of this class of ligands with their receptor. 5,6
High potent and selective arylpiperazine derivatives as ligands for the 5-HT1A receptor
Bioorganic & Medicinal Chemistry Letters, 2000
AbstractÐThis paper reports the synthesis and anities on the 5-HT 1A versus the a 1 A receptors of new arylpiperazinylalkylthiothienopyrimidine and thiadiazole derivatives 16±24. Arylpiperazines 16±23 show anities values in the nanomolar range for the 5-HT 1A receptor. The compound 16 is highly potent (K i 0.26 nM, selectivity 28), the derivatives 20 and 21 are less potent, but highly selective (K i 9.40 and 5.06 nM, selectivity 207 and 73, respectively). #
We performed a detailed in vitro pharmacological characterization of two arylpiperazine derivatives, compound N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1piperazinehexanamide (LP-211) previously identified as a high-affinity brain penetrant ligand for 5-hydroxytryptamine (serotonin) type 7 (5-HT 7 ) receptors, and its analog N-benzyl-4-(2-diphenyl)-1-piperazinehexanamide (MEL-9). Both ligands exhibited competitive displacement of [ 3 H]-(2R)-1-[(3-hydroxyphenyl) sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine ([ 3 H]-SB-269970) radioligand binding and insurmountable antagonism of 5-carboxamidotryptamine (5-CT)-stimulated cyclic adenosine monophosphate (cAMP) signaling in human embryonic kidney (HEK293) cells stably expressing human 5-HT 7 receptors. They also inhibited forskolin-stimulated adenylate cyclase activity in 5-HT 7expressing HEK293 cells but not in the parental cell line. The compounds elicited long-lasting (at least 24 h) concentration-dependent inhibition of radioligand binding at 5-HT 7 -binding sites in whole-cell radioligand binding assays, after pretreatment of the cells with the compounds and subsequent compound removal. In cAMP assays, pretreatment of cells with the compounds rendered 5-HT 7 receptors unresponsive to 5-CT and also rendered 5-HT 7 -expressing HEK293 cells unresponsive to forskolin. Compound 1-(2-biphenyl)piperazine (RA-7), a known active metabolite of LP-211 present in vivo, was able to partially inhibit 5-HT 7 radioligand binding in a long-lasting irreversible manner. Hence, LP-211 and MEL-9 were identified as high-affinity long-acting inhibitors of human 5-HT 7 receptor binding and function in cell lines. The detailed in vitro characterization of these two pharmacological tools targeting 5-HT 7 receptors may benefit the study of 5-HT 7 receptor function and it may lead to the development of novel selective pharmacological tools with defined functional properties at 5-HT 7 receptors.
Related topics
Cited by
Journal of Enzyme Inhibition and Medicinal Chemistry, 2015
A series of new 7-arylpiperazinylalkyl-1,3-dimethyl-purine-2,6-dione derivatives with diversified 8-amino substituent in 8 position was synthesized and their 5-HT 1A , 5-HT 2A , 5-HT 6 , 5-HT 7 , and D 2 receptor affinities were determined. The binding study allowed identifying some potent 5-HT 1A /5-HT 2A /5-HT 7 /D 2 ligands. The most interesting because of their multireceptor profile were 8-piperidine (30-35) and 8-dipropylamine (45-47) analogs with four and five carbon aliphatic linkers. The selected compounds 24, 31, 34, 39, 41, 43, 45, and 46 in the functional in vitro evaluation for all targeted receptors showed significant partial D 2 agonist, partial 5-HT 1A agonist, and 5-HT 2A antagonist properties. The advantageous in vitro affinity of compound 34 for 5-HT 1A and D 2 receptors has been explained by means of molecular modeling, taking into consideration its partial agonist activity towards the latter one. In behavioral studies, compounds 32 and 34 revealed antipsychotic-like properties, significantly decreasing D-amphetamine-induced hyperactivity in mice.
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.
Journal of Heterocyclic Chemistry, 2007
Syntheses of the N-substituted butyl derivatives of 1,8-naphthalimide (1-8), containing various arylpiperazines, tetrahydroisoquinoline and methylhomopiperazine moieties attached at 4-position of the butyl chain have been described. Biological activities were evaluated in vitro for their ability to bind to serotonin 5-HT 1A and 5-HT 7 receptors. Due to the structural similarity of derivatives 1-8 to psychotropic agents, the pharmacological properties of target compounds were predicted using PASS program.