Novel Mannich Bases, 5‐Arylimidazolidine‐2,4‐dione Derivatives with Dual 5‐HT1A Receptor and Serotonin Transporter Affinity

A computer aided ligand design study of imidazolidine‐2,4‐dione derivatives was conducted in order to obtain compounds with dual 5‐HT_1A receptor and serotonin transporter (SERT) affinity. According to molecular modeling results, series of Mannich bases were chosen and synthesized. Investigated compounds were tested for 5‐HT_1A, 5‐HT_2A, α₁ and SERT affinity. Two selected compounds ( 5 , 9 ) were characterized in functional experiments and possessed a pharmacological profile which may enhance SERT blocking efficacy – 5‐HT_1A partial agonism and 5‐HT_2A antagonism in one molecule. Furthermore these compounds displayed satisfactory selectivity over adrenergic α₁ receptors. The most promising compounds, 5‐arylimidazolidine‐2,4‐dione derivatives with 4‐(3‐chlorophenyl)piperazinylmethyl moiety were tested for antidepressant and anxiolytic activity. In particular, compound 5 (5‐(2‐methoxyphenyl)‐3‐{1‐[4‐(3‐chlorophenyl)piperazin‐1‐yl]methyl}‐imidazolidine‐2,4‐dione), tested in the forced swim test in mice, exhibited a favorable antidepressant‐like profile without affecting spontaneous locomotor activity.     

Solid‐Supported Synthesis and 5‐HT7/5‐HT1A Receptor Affinity of Arylpiperazinylbutyl Derivatives of 4,5‐dihydro‐1,2,4‐triazine‐6‐(1H)‐one

A series of arylpiperazinylbutyl derivatives of 4,5‐dihydro‐1,2,4‐triazine‐6(1H)‐ones was designed and synthesized according to the new solid‐supported methodology. In this approach, triazinone scaffold was constructed from the Fmoc‐protected glycine. The library representatives showed different levels of affinity for 5‐HT₇ and 5‐HT_1A receptors; compounds 13 , 14 and 18 – 20 were classified as dual 5‐HT₇/5‐HT_1A receptors ligands. The structure–affinity relationship analysis revealed that the receptor affinity and selectivity of the tested compounds depended on the kind of substituent in position 3 of triazinone fragment as well as substitution pattern of the phenylpiperazine moiety.     

Quinolinesulfonamides of Aryloxy‐/Arylthio‐ethyl Piperidines: Influence of an Arylether Fragment on 5‐HT1A/5‐HT7 Receptor Selectivity

The solid‐phase synthesis of a new series of 19 biomimetics of long‐chain arylpiperazines, namely flexible quinoline sulfonamides of aryl(heteroaryl)oxy‐/heteroarylthio‐ethyl 4‐aminomethylpiperidines, is reported. Various structural modifications applied followed by biological evaluation for 5‐HT_1A, 5‐HT₆, and 5‐HT₇ receptors gave further support of a possible replacement of arylpiperazine with aryloxy‐/arylthio‐ethyl derivatives of alicyclic amines and control of receptor selectivity upon diversification in the aryl(heteroaryl)oxy‐/heteroarylthio‐ethyl fragment.     

A Search for New 5-HT1A/5-HT2A Receptor Ligands. In Vitro and in vivo Studies of 1-[ω-(4-Aryl-1-piperazinyl)alkyl]indolin-2(1H)-ones

A series of 1-[ω-(4-aryl-1-piperazinyl)alkyl]indolin-2(1H)-one derivatives 2–14 was synthesized in order to obtain ligands with a dual 5-HT_1A/5-HT_2A activity. The majority of those compounds ( 2–5, 7, 10–13 ) exhibited a high 5-HT_1A (K_i = 2 – 44 nM) and/or 5-HT_2A affinity (K_i = 51 and 39 for 5 and 7 , respectively). Induction of lower lip retraction (LLR) and behavioral syndrome and inhibition of these efects evoked by 8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) were used for determination the agonistic and antagonistic activity, respectively, at 5-HT_1A receptors. The 5-HT_2A antagonistic activity was assessed by the blocking effect on the head twitches induced by (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in mice. Two of the tested compounds, 1-{3-[4-(3-chlorophenyl)-1-piperazinyl]propyl}-6-fluoroindolin-2(1H)-one ( 5 ) and 1-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}indolin-2(1H)-one ( 7 ), demonstrated a high 5-HT_1A/5-HT_2A affinity and an in vivo antagonistic activity towards both receptor subtypes.     

3-(ω-Aminoalkyl)-5,5-dialkyl(or spirocycloalkyl-1′,5-)hydantoins as New 5-HT1A and 5-HT2A Receptor Ligands

A series of new 3-(ω-aminoalkyl)-5,5-disubstituted hydantoins, containing 1-phenylpiperazine, 1-(o-methoxyphenyl)piperazine or 1,2,3,4-tetrahydroisoquinoline fragments, were synthesized by standard alkylation procedures and their 5-HT_1A and 5-HT_2A receptor affinities were determined. It has been shown that the investigated derivatives are recognized by 5-HT_1A and 5-HT_2A receptors due to the presence of a 1-arylpiperazine fragment; however, the terminal hydantoin moiety plays an important role in stabilization of the receptor-ligand complex. It has also been found that the two 1-phenylpiperazine derivatives 32 and 36 are new, selective 5-HT_2A receptor ligands (K_i = 34 and 37 nM, respectively), whereas the derivative of 1-(o-methoxyphenyl)piperazine ( 38 ) is a new, highly potent 5-HT_1A receptor ligand (K_i = 0.51 nM) with a moderate affinity for 5-HT_2A receptors (K_i = 213 nM).     

5‐HT modulates the rat mesenteric vasopressor outflow by 5‐HT1D sympatholytic receptors

5‐hydroxytryptamine (5‐HT) modulates noradrenergic activity in different cardiovascular territories, but its effect on the mesenteric vasopressor outflow has not yet been clarified. This study investigated the in vivo serotonergic influence, characterizing 5‐HT receptors implicated, in sympathetic innervation of mesenteric vasculature. Wistar rats were anaesthetised and prepared for the in situ autoperfused rat mesentery, monitoring systemic blood pressure (SBP), heart rate (HR) and mesenteric perfusion pressure (MPP). Electrical stimulation of mesenteric sympathetic nerves resulted in frequency‐dependent increases in MPP (9 ± 1.6, 25.7 ± 3.9 and 60.2 ± 5 mmHg for 2, 4 and 8 Hz, respectively), without altering SBP or HR. 5‐HT (1‐25 μg/kg), 5‐carboxamidotryptamine (5‐HT_1/7 agonist; 25 μg/kg) or L‐694,247 (5‐HT_1D agonist; 1‐25 μg/kg) i.a. bolus inhibited vasopressor responses by mesenteric nerves electrical stimulation, unlike i.a. bolus of agonists 8‐OH‐DPAT (5‐HT_1A), CGS‐12066B (5‐HT_1B), BRL 54443 (5‐HT_1e/1F), α‐methyl‐5‐HT (5‐HT₂), 1‐PBG (5‐HT₃), cisapride (5‐HT₄) or AS‐19 (5‐HT₇) (25 μg/kg each). Interestingly, i.a. L‐694,247 (25 μg/kg) also reduced the exogenous norepinephrine‐induced vasoconstrictions. Pretreatment with selective 5‐HT_1D receptor antagonist, LY310762 (1 mg/kg, i.v.), completely abolished L‐694,247‐ and 5‐HT‐induced mesenteric sympathoinhibition. Furthermore, ELISA analysis confirmed 5‐HT_1D receptors expression in mesenteric artery. These findings suggest that serotonergic mechanisms‐induced sympathoinhibition of mesenteric noradrenergic outflow is mediated by pre and/or postjunctional 5‐HT_1D receptors.     

Structure-Activity Relationship Studies of CNS Agents,Part 31[1]: Analogs of MP 3022 with a Different Number of Nitrogen Atoms in the Heteroaromatic Fragment — New 5-HT1A Receptor Ligands

Two series of new MP 3022 analogs, i.e. 1-(o-methoxyphenyl)-4-n-propylpiperazines ( 3, 4a, 4b, 6–9 , and 12–13 ) and 2-(n-propyl)-1,2,3,4-tetrahydroisoquinolines ( 5a, 5b, 11a , and 11b ) containing a terminal heteroaromatic system with a different number of nitrogen atoms, were synthesized and their 5-HT_1A/5-HT_2A and α₁ receptor affinity was assayed. The majority of investigated piperazines may be classified as non-selective 5-HT_1A/5-HT_2A/α₁ receptor ligands. Compounds 3, 4a, 4b, 7–9a with the highest affinity for 5-HT_1A receptors (K_i = 4–54 nM) were tested in vivo. Their functional activity was differentiated; while 3, 8 , and 9a behaved like weak antagonists of postsynaptic 5-HT_1A receptors, 4b and 7 may be classified as potential partial 5-HT_1A receptor agonists. Isomer 4a has characteristic features of a potential weak postsynaptic 5-HT_1A receptor agonist.     

Synthesis of 3H‐ and 14C‐labeled AR‐A000002, a new and selective 5‐HT1B/1D ligand

AR‐A000002 is a novel and selective high‐affinity 5‐HT_1B/1D receptor antagonist. The compound has been shown to enhance 5‐HT turnover in the guinea pig brain in vivo and to increase the extracellular concentration of 5‐HT and the metabolite 5‐hydroxyindoleacetic acid (5‐HIAA) in guinea pig frontal cortex. The observed effects suggest that the compound could be used for the treatment of affective disorders. The syntheses of labeled AR‐A000002 analogues as needed for the further pharmacological evaluation of this selective 5‐HT_1B/1D antagonist, are described. Copyright © 2004 John Wiley & Sons, Ltd.     

Aporphinoid Antagonists of 5‐HT2A Receptors: Further Evaluation of Ring A Substituents and the Size of Ring C

A series of ring A‐modified analogs of nantenine as well as structural variants in ring C were synthesized and evaluated for antagonist activity at 5‐HT_2A and α_1A receptors. Halogenation improves 5‐HT_2A antagonist potency in molecules containing a C1 methoxyl/C2 methoxyl or C1 methoxyl/C2 hydroxyl moiety. Bromination or iodination (but not chlorination) with the latter moiety also significantly increased α_1A antagonist potency. Homologation or contraction of ring C adversely affected antagonist activity at both receptors, implying that a six‐membered ring C motif is beneficial for high antagonist potency at both receptors. Molecular docking studies suggest that the improved antagonist activity (by virtue of improved affinity) of C3‐halogenated aporphines in this study is attributable to favorable interactions with the C3 halogen and F339 and/or F340.     

In the search for a lead structure among series of potent and selective hydantoin 5‐HT7R agents: The drug‐likeness in vitro study

Since the year 1993, when 5‐HT₇ receptor (5‐HT₇R) was discovered, there is no selective 5‐HT₇R ligand introduced to the pharmaceutical market. One out of the main reasons disqualifying the 5‐HT₇R ligands is weak drugability properties, including metabolic instability or low permeability. This study is focused on the search of a lead compound by “drug‐likeness” estimation of the first series of selective and potent 5‐HT₇R ligands among 5‐(4‐fluorophenyl)‐3‐(2‐hydroxy‐3‐(4‐aryl‐piperazin‐1‐yl)propyl)‐5‐methylimidazolidine‐2,4‐dione derivatives ( 11–16 ). The most important drugability parameters, i.e., permeability, metabolic stability, and safety, have been evaluated. The main metabolic pathways were determined. The forced swim test (FST) in mice was performed as a primary in vivo assay for compound 13 and the reference 2 . The experiments showed promising drug‐like properties for all ligands, with special attention to the benzhydryl (diphenylmethyl) derivative 13 . The studies have also indicated in vivo activity of the compound 13 that was observed as a significant and specific antidepressant‐like activity in the FST. Taking into account the beneficial properties of 13 , i.e., good drug‐like parameters, the significant antagonistic action, high selectivity to 5‐HT₇R, and its in vivo antidepressant‐like activity, the compound should be considered as a new lead in the search for drugs acting on CNS via 5‐HT₇ receptor.     

N‐[3‐[4‐(2‐methoxyphenyl) piperaziny‐1‐yl]propyl]cyclam: synthesized as a potential 5‐HT1A receptor ligand and labelled with 99mTc‐nitrido core

This paper reports the synthesis of new potential 5‐HT_1A receptor ligand N‐[3‐[4‐(2‐methoxyphenyl)piperaziny‐1‐yl]propyl]cyclam (MPPC) and radiolabelling of it with ^99mTc‐nitrido core. The novel neutral complex ^99mTcN‐MPPC combines 1,4,8,11‐tetraazacyclotetradecane (cyclam) ligand as chelate moiety for ^99mTc‐nitrido with a 1‐(2‐methoxyphenyl)piperazine moiety derived from WAY 100635 via a 3‐carbon alkyl chain. This provided a reliable and reproducible method for attaching the technetium to the pharmacophore moiety of WAY 100635. ^99mTcN‐MPPC was prepared by a two‐step procedure and the radiochemical purity was found to be greater than 95%. It was hydrophilic and stable for at least 4 h at room temperature. In vivo stability study in normal rats showed that no degradation of ^99mTcN‐MPPC was found in deproteinated blood samples at 2 h post‐injection. This effective ^99mTc‐labelling strategy for obtaining neutral ^99mTc nitrido complexes would be a useful tool to prepare new SPECT agents to image 5‐HT_1A receptor with cyclam conjugated ligands. Copyright © 2008 John Wiley & Sons, Ltd.     

Structure Activity Relationship of Homochiral 7-Substituted 1-Aminoindans as 5-HT1A Receptor Ligands

A series of homochiral 7-substituted 1-aminoindans was prepared by means of asymmetric reductive amination from racemic 7-substituted 1-indanones via E-imines and E-imine/ enamine mixtures, respectively, and subjected to 5-hydroxytryptamine (5-HT) receptor subtype binding studies. The ee’s of the title compounds were determined by HPLC of the corresponding Mosher’s amides and range from 96 to 99.9%. The absolute configuration was elucidated by means of correlation CD spectroscopy. On the basis of the pK_I values obtained from various test systems, structure activity relationships have been established with respect to the absolute configuration, degree of N-alkylation, and the type of 7-substituents. The tested 1-aminoindans show the highest affinity to the 5-HT_1A receptor, with decreasing magnitude for the 5-HT_2A, 5-HT_1D, and 5-HT_2C receptors. The highest affinities for the 5-HT_1A receptor were observed for the R-(–)-7-propoxy-1-(di-n-propylamino)indan hydrochloride (R-(–)-30), S,S′-(+)-7-benzylamido-1-(1-phenylethylamino)indan hydrochloride [S,S′-(+)- 19 ] and R-(–)-7-methoxy-1-(di-n-propylamino)indan hydrogenembonate (R-(–)- 29 ) with pK_I = 7.07 ± 0.19, 6.40 ± 0.09, and 6.22 ± 0.10, respectively, in comparison to 8-OH-DPAT with pK_I = 8.70 ± 0.30. Nearly all other compounds showed low affinity at all 5-HT receptors tested. The three above mentioned ligands were tested on HeLa cells (cell line HA6) expressing recombinant human 5-HT_1A receptors for their effects on forskolin-stimulated cAMP accumulation in intact cells. Both the di-n-propylamino substituent bearing R-(–)- 30 and R-(–)- 29 acted as efficacious agonists with a pEC₅₀ value of 5.89 ± 0.20 for R-(–)- 30 compared to 5-HT with a pEC₅₀ value of 8.06 ± 0.14. S,S′-(+)- 19 with the 1-phenylethylamino substituent was devoid of intrinsic activity up to the highest tested concentration (10 μM).     

2‐Amino‐3‐(1‐(4‐(4‐(2‐methoxyphenyl) piperazine‐1‐yl)butyl)‐1H‐1,2,3‐triazol‐4‐yl) propanoic acid: synthesized, 99mTc‐tricarbonyl labeled,and bioevaluated as a potential 5HT1A receptor ligand

To develop a novel 5HT_1A receptor imaging agent, a new methoxyphenyl piperazine derivative was synthesized and radiolabeled with ^99mTc‐tricarbonyl precursor. We used the Cu (I)‐catalyzed cycloaddition of azide and terminal alkynes to synthesize 1, 2, 3 triazole as the metal chelating system. This synthesis provided reliable and reproducible method to attach technetium to the methoxyphenyl piperazine moiety. ^99mTc‐tricabonyl labeling of ligand was performed at high radiochemical purity (greater than 95%). The radiolabeled compound was stable at least 24 h in room temperature. In vitro stability study in human serum albumin showed more than 90% stability in 37 °C incubation for 6 h. Biodistribution studies in rat have shown brain hippocampus uptake of 0.31 ± 0.02 %ID/g at 5‐min post‐injection. The favorable in vitro/in vivo stability, lipophilicity, and biodistribution profiles suggest that this radioconjugate is a good candidate for further exploration of its potential clinical application. Copyright © 2012 John Wiley & Sons, Ltd.