Potent 5-HT1A Receptor Antagonist Research Articles

Structural modelling and in silico pharmacology of β-carboline alkaloids as potent 5-HT1A receptor antagonists and reuptake inhibitors

Serotonin (5-HT) antagonists and reuptake inhibitors (SARIs) are atypical antidepressants for managing major depressive disorder. They are oftentimes applied as adjuvants for ameliorating aftereffects of SSRI antidepressants including insomnia and sexual dysfunction. The few available candidates of this class including lorpiprazole and trazodone also display some daunting side effects, making a continuous search for improved alternatives essential. Natural β-carboline alkaloids (NβCs) are interestingly renowned with broad pharmacological spectrum against several neuropsychiatric disorders including depression. However, their potentials as SARIs remain underexplored. In this study, 982 NβCs retrieved from the Ambinter-Greenpharma (Amb) database were virtually screened for potent SARI alternatives using computational and biocheminformatics approaches: homology modelling of 5-HT1A receptor, Glide HTVS, SP and XP molecular docking, molecular dynamics (MD) simulation, ADMET and mutagenicity predictions. The homology receptor was validated as a good representative of human 5HT1A receptor using the RCSB structure validation and quality protocols. From the virtual screening against the 5-HT1A receptor, Amb ligands, Amb18709727 and Amb37857532 showed higher binding affinities by XP scores of −8.725 and −7.976 kcal/mol, and MMGBSA of −87.972 and −107.585 kcal/mol respectively compared to lorpiprazole, a reference SARI with XP score and MMGBSA of −6.512 and −62.788 kcal/mol respectively. They maintained ideal contacts with pharmacologically essential amino acid residues implicated in SARI mechanisms and expressed higher stability and compactness than lorpiprazole throughout the trajectories of 100 ns MD simulation. They also displayed interesting ADME, druggability, low toxicity and mutagenicity profiles, ideal for CNS drug prospects, thus, recommended as putative SARI candidates for further study.

Design and Synthesis of Novel Aminoalkanamides Targeting Neurodegeneration and Symptoms of Alzheimer's Disease.

There is currently no drug that slows the process of neurodegeneration or alleviates the cognitive and depressive symptoms in patients with Alzheimer's disease. Due to the increasing number of Alzheimer's patients, there is an urgent need to develop novel drugs with neuroprotective, procognitive, and antidepressant properties. The aim of this study was to design, synthesize, and evaluate novel aminoalkanamides with serotonin 5-HT1A/5-HT;7 receptor affinity and phosphodiesterase (PDE) inhibitory activity as a new approach to combat neurodegeneration and symptoms of Alzheimer's disease. The newly designed compounds were synthesized using classical methods of organic chemistry and tested in vitro for their receptor affinity, functional profile, enzyme inhibition, and ADME properties. The neuroprotective effect against H2O2-induced increase of reactive oxygen species level was tested in SH-SY5Y cells. The novel object recognition and forced swimming tests were used to evaluate the procognitive and antidepressant activity, respectively. Synthesized aminoalkanamides were characterized as potent 5-HT1Areceptor antagonists with additional 5-HT7 receptor antagonistic properties and PDE4B inhibitory activity. Selected compound 15 showed neuroprotective, procognitive, and antidepressant properties. In addition, compound 15 revealed suitable ADME properties expressed as good membrane permeability and high metabolic stability. This study revealed a new class of compounds that may be useful in the search for an effective drug in the alleviation of neurodegeneration and symptoms of Alzheimer's disease.

New 99m Tc(CO)3 -radiolabeled arylpiperazine pharmacophore as potent 5HT1A serotonin receptor radiotracer: Docking studies, chemical synthesis, radiolabeling, and biological evaluation.

In spite of previous efforts, there is lack of a radiotracer for imaging the 5HT1A receptor density in human brain, which is involved in several neurological brain disorders. The aim of this study was to prepare a new derivative of 1-(2-methoxyphenyl)piperazine (MPP) as a main chemical structure of 5HT1A receptor antagonist with 3-carbon linker and radiolabeled by [99m Tc][Tc(CO)3 (H2 O)3 ]+ precursor. Docking studies before chemical synthesis showed similar fashion of interaction for both WAY100635 (potent 5HT1A receptor antagonist) and new designed ligand, despite of addition of 99m Tc(CO)3 group in the structure of new ligand. MPP-(CH2 )3 -N3 was synthesized via three efficient and reliable chemical synthesis steps (more than 80% yield) then radiolabeled by addition of 2-ethynylpyridine and [99m Tc][Tc(CO)3 (H2 O)3 ]+ precursor in one pot procedure (more than 95% radiochemical efficiency) through click chemistry method. After incubation, radiotracer was found stable in vitro up to 2hours. Binding assays showed about 33% specific binding of radiotracer to the 5HT1A receptors. Brain biodistribution studies indicated (0.26±0.05)% ID/g hippocampus uptake at 30minutes post injection, which its specificity was verified through blocking studies. These results suggested that new designed radioligand might serve as a potent SPECT imaging agent to estimate status of 5HT1A receptors.

11C-CUMI-101, a PET Radioligand, Behaves as a Serotonin 1A Receptor Antagonist and Also Binds to α1 Adrenoceptors in Brain

The PET radioligand (11)C-CUMI-101 was previously suggested as a putative agonist radioligand for the serotonin 1A (5-hydroxytryptamine 1A [5-HT1A]) receptor in recombinant cells expressing human 5-HT1A receptor. However, a recent study showed that CUMI-101 behaved as a potent 5-HT1A receptor antagonist in rat brain. CUMI-101 also has moderate affinity (Ki = 6.75 nM) for α1 adrenoceptors measured in vitro. The current study examined the functional properties and selectivity of CUMI-101, both in vitro and in vivo. The functional assay was performed using (35)S-GTPγS (GTP is guanosine triphosphate) in primate brains. The cross-reactivity of CUMI-101 with α1 adrenoceptors was performed using in vitro radioligand binding studies in rat, monkey, and human brains as well as in vivo PET imaging in mouse, rat, and monkey brains. CUMI-101 did not stimulate (35)S-GTPγS binding in primate brain, in contrast to 8-OH-DPAT, a potent 5-HT1A receptor agonist. Instead, CUMI-101 behaved as a potent 5-HT1A receptor antagonist by dose-dependently inhibiting 8-OH-DPAT-stimulated (35)S-GTPγS binding. Both in vitro and in vivo studies showed that CUMI-101 had significant α1 adrenoceptor cross-reactivity. On average, across all 3 species examined, cross-reactivity was highest in the thalamus (>45%) and lowest in the neocortex and cerebellum (<10%). PET imaging further confirmed that only preblocking with WAY-100635 plus prazosin decreased (11)C-CUMI-101 brain uptake to that of self-block. CUMI-101 behaves as a 5-HT1A receptor antagonist in primate brain, with significant, regional-dependent α1 adrenoceptor cross-reactivity, limiting its potential use as a PET radioligand in humans.

Serotonergic modulation of LTP at excitatory and inhibitory synapses in the developing rat visual cortex

The stability and efficacy of neuronal circuits are achieved through a detailed balance between pyramidal cell and interneuron activities. Interestingly, the neocortical excitatory–inhibitory (E–I) balance is actively maintained at the soma of Layer 5 pyramidal neurons which receive 20% of excitation and 80% of inhibition after dendritic integration, and this is not affected by changes in synaptic strength. To infer the role of serotonergic neuromodulation on the activity-dependent maintenance of the E–I balance, we performed continuous voltage clamp measurements of stimulation-locked conductance dynamics in Layer 5 pyramidal neurons before and after long-term potentiation (LTP) induction, together with chronic or acute manipulation of serotonin function. When a theta-burst stimulation was applied in Layer 2/3 of 5-HT depleted cortical slices (after in vivo treatment with the tryptophan hydroxylase inhibitor p-chlorophenylalanine (pCPA)), or after in vitro perfusion of the potent 5-HT1A receptor antagonist WAY-100,635, we observed a persistent shift of the ratio between excitation and inhibition toward more inhibition. This was due to a strong LTP of inhibition co-aligned with a weak LTP of excitation, whereas the same protocol caused a similar potentiation of excitatory and inhibitory inputs when applied in control slices. In contrast, neither excitatory nor inhibitory postsynaptic currents were potentiated when LTP protocols were delivered in the presence of either the selective serotonin reuptake inhibitor citalopram or the 5-HT1A receptor agonist 8-OH-DPAT. This is the first demonstration that serotonergic neuromodulation is crucial for the maintenance of the neocortical E–I balance during high-frequency regimes.

An improved one-pot procedure for the preparation of [ 11C-carbonyl]-WAY100635

A simple one-pot procedure for the preparation of [ 11C-carbonyl]-WAY100635, a potent 5HT1A receptor antagonist, was developed. The procedure involves the trapping of 11CO 2 in a tetrahydrofuran (THF) solution of cyclohexylmagnesium chloride, elimination of excess Grignard reagents with anhydrous HCl, reaction with SOCl 2, and the reaction of the resulting acid chloride with WAY100634 (2 mg) and triethylamine (20 μL) in THF. The total synthesis time is 45 min. Starting from 1326 ± 173 mCi of 11CO 2, the average amount of [ 11C-carbonyl]-WAY100635 ( n =40 ) at end-of-synthesis (EOS) was 30 ± 13 mCi (2.3% radiochemical yield), or 148 ± 61 mCi (11%) at end-of-bombardment (EOB). The radiochemical purity was >99%, and the specific activity was 3.6 ± 1.9 Ci/μmol (EOS, n =40 ), or 21.3 ± 9.8 Ci/μmol at EOB. This method is reliable and flexible for routine clinical studies.