Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT1A and 5-HT7 G protein-coupled receptor affinity, 3D-QSAR and molecular modeling

Perry, Charles K.; Casey, Austen B.; Felsing, Daniel E.; Vemula, Rajender; Zaka, Mehreen; Herrington, Noah B.; Cui, Meng; Kellogg, Glen E.; Canal, Clinton E.; Booth, Raymond G.

doi:10.1016/j.bmc.2019.115262

Cited by 16 publications

(23 citation statements)

References 40 publications

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“…Some 2‐aminotetralins substituted at the C(5)‐ or C(8)‐position have high affinity at 5‐HT 1A and 5‐HT 7 receptors (Perry et al, 2020), while others target D 2 ‐like receptors (Seiler & Markstein, 1984). Furthermore, affinity at 5‐HT 2B and α 1B ‐ adrenoceptors may predict ligand promiscuity (Peters et al, 2012) and high affinity antagonism of central α 1A/1B ‐adrenoceptors is associated with adverse events such as orthostatic hypotension, dizziness and sedation (Andersson & Gratzke, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Details on assay conditions, radioligand, non‐specific binding and receptor expression are provided in Table S1. Ligand affinity was assessed using established methodology (Perry et al, 2020; Roth, 2013) and 2–5 μg of protein per well, determined by the Pierce bicinchoninic acid protein assay according to the manufacturer's protocol (Thermo Scientific). Saturation binding experiments were performed in triplicate across eight concentrations.…”

Section: Methodsmentioning

confidence: 99%

“…Transfections were performed for 48 h. This represents an economic modification of our previous transfection methods using lipofectamine or Turbofect (Invitrogen, #11668027 and Thermo Scientific, #R0532, respectively), which gave similar levels of expression for the receptors studied here. Cell membranes were homogenized as previously described (Perry et al, 2020).…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

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A new class of 5‐HT_2A/5‐HT_2C receptor inverse agonists: Synthesis, molecular modeling, in vitro and in vivo pharmacology of novel 2‐aminotetralins

Casey

Mukherjee

McGlynn

et al. 2022

British J Pharmacology

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Background and Purpose The 5‐HT receptor subtypes 5‐HT2A and 5‐HT2C are important neurotherapeutic targets, though, obtaining selectivity over 5‐HT2B and H1 receptors is challenging. Here, we delineated molecular determinants of selective binding to 5‐HT2A and 5‐HT2C receptors for novel 4‐phenyl‐2‐dimethylaminotetralins (4‐PATs). Experimental Approach We synthesized 42 novel 4‐PATs with halogen or aryl moieties at the C(4)‐phenyl meta‐position. Affinity, function, molecular modeling and 5‐HT2A receptor mutagenesis studies were performed to understand structure–activity relationships at 5‐HT2‐type and H1 receptors. Lead 4‐PAT‐type 5‐HT2A/5‐HT2C receptor inverse agonists were compared with pimavanserin, a selective 5‐HT2A/5‐HT2C receptor inverse agonist approved to treat Parkinson's disease‐related psychosis, in the mouse head twitch response and locomotor activity assays, models relevant to antipsychotic drug development. Key Results Most 4‐PAT diastereomers in the (2S,4R)‐configuration bound non‐selectively to 5‐HT2A, 5‐HT2C and H1 receptors, with >100‐fold selectivity over 5‐HT2B receptors, whereas diastereomers in the (2R,4R)‐configuration bound preferentially to 5‐HT2A over 5‐HT2C receptors and had >100‐fold selectivity over 5‐HT2B and H1 receptors. Results suggest that G2385.42 and V2355.39 in 5‐HT2A receptors (conserved in 5‐HT2C receptors) are important for high affinity binding, whereas interactions with T1945.42 and W1584.56 determine H1 receptor affinity. The 4‐PAT analog (2S,4R)‐4‐(4'‐(dimethylamino)‐[1,1'‐biphenyl]‐3‐yl)‐N,N‐dimethyl‐1,2,3,4‐tetrahydronaphthalen‐2‐amine, (2S,4R)‐2k, a potent and selective 5‐HT2A/5‐HT2C receptor inverse agonist, had activity like pimavanserin in the mouse head twitch response assay but was distinct in not suppressing locomotor activity. Conclusions and Implications The novel 4‐PAT chemotype can yield selective 5‐HT2A/5‐HT2C receptor inverse agonists for antipsychotic drug development by optimizing ligand–receptor interactions in transmembrane domain 5. Chirality can be exploited to attain selectivity over H1 receptors, which may circumvent sedative effects.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Cell Culture and Transfectionmentioning

confidence: 99%

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A new class of 5‐HT_2A/5‐HT_2C receptor inverse agonists: Synthesis, molecular modeling, in vitro and in vivo pharmacology of novel 2‐aminotetralins

Casey

Mukherjee

McGlynn

et al. 2022

British J Pharmacology

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“…After developing the lead compound, (+)-5-FPT, [ 101 ] Perry et al synthesized more derivatives and pursued 3D-QSAR and molecular docking studies to understand important structural requirements. The authors found that a steric appendage either at C5- or chiral C2-position enhances selectivity for 5-HT 7 R or 5-HT 1A R, respectively [ 103 ].…”

Section: 5-ht 7 Receptor (5-ht 7 ...mentioning

confidence: 99%

Serotonin Receptors as Therapeutic Targets for Autism Spectrum Disorder Treatment

Lee

Choo

Jeon

2022

IJMS

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Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by repetitive and stereotyped behaviors as well as difficulties with social interaction and communication. According to reports for prevalence rates of ASD, approximately 1~2% of children worldwide have been diagnosed with ASD. Although there are a couple of FDA (Food and Drug Administration)—approved drugs for ASD treatment such as aripiprazole and risperidone, they are efficient for alleviating aggression, hyperactivity, and self-injury but not the core symptoms. Serotonin (5-hydroxytryptamine, 5-HT) as a neurotransmitter plays a crucial role in the early neurodevelopmental stage. In particular, 5-HT has been known to regulate a variety of neurobiological processes including neurite outgrowth, dendritic spine morphology, shaping neuronal circuits, synaptic transmission, and synaptic plasticity. Given the roles of serotonergic systems, the 5-HT receptors (5-HTRs) become emerging as potential therapeutic targets in the ASD. In this review, we will focus on the recent development of small molecule modulators of 5-HTRs as therapeutic targets for the ASD treatment.

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“…[1] Within the diverse range of N-containing optically active molecules, 2-aminotetralin and 3-aminochroman derivatives are much sought after structural motifs found in a wide variety of bioactive molecules and market-approved active pharmaceutical ingredients (APIs). [2][3][4][5] Representative examples of these compounds are the former drug candidates Ebalzotan, [6] Alnespirone [7] and Robalzotan, [8] studied as potential antidepressant and anxiolytic treatments due to their antagonistic and agonistic effects at the 5-HT 1A receptor. Particular interest has been shown in 5-OH-DPAT [9] and Rotigotine [10] as therapeutic ingredients for Parkinsons disease, with the latter (commercially known as Neupro ) reaching a market value of E 311 million in 2020 (Figure 1).…”

Section: Chiralaminesoccupyaprominentroleduetotheirsyntheticmentioning

confidence: 99%

Synthesis of Pharmaceutically Relevant 2‐Aminotetralin and 3‐Aminochroman Derivatives via Enzymatic Reductive Amination

et al. 2021

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2-Aminotetralin and 3-aminochroman derivatives are key structural motifs present in a wide range of pharmaceutically important molecules. Herein, we report an effective biocatalytic approach towards these molecules through the enantioselective reductive coupling of 2-tetralones and 3chromanones with a diverse range of primary amine partners. Metagenomic imine reductases (IREDs) were employed as the biocatalysts, obtaining high yields and enantiocomplementary selectivity for > 15 examples at preparative scale, including the precursors to Ebalzotan, Robalzotan, Alnespirone and 5-OH-DPAT. We also present a convergent chemo-enzymatic total synthesis of the Parkinsons disease therapy Rotigotine in 63 % overall yield and 92 % ee.

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Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT1A and 5-HT7 G protein-coupled receptor affinity, 3D-QSAR and molecular modeling

Cited by 16 publications

References 40 publications

A new class of 5‐HT_2A/5‐HT_2C receptor inverse agonists: Synthesis, molecular modeling, in vitro and in vivo pharmacology of novel 2‐aminotetralins

A new class of 5‐HT_2A/5‐HT_2C receptor inverse agonists: Synthesis, molecular modeling, in vitro and in vivo pharmacology of novel 2‐aminotetralins

Serotonin Receptors as Therapeutic Targets for Autism Spectrum Disorder Treatment

Synthesis of Pharmaceutically Relevant 2‐Aminotetralin and 3‐Aminochroman Derivatives via Enzymatic Reductive Amination

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Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT1A and 5-HT7 G protein-coupled receptor affinity, 3D-QSAR and molecular modeling

Cited by 16 publications

References 40 publications

A new class of 5‐HT2A/5‐HT2C receptor inverse agonists: Synthesis, molecular modeling, in vitro and in vivo pharmacology of novel 2‐aminotetralins

A new class of 5‐HT2A/5‐HT2C receptor inverse agonists: Synthesis, molecular modeling, in vitro and in vivo pharmacology of novel 2‐aminotetralins

Serotonin Receptors as Therapeutic Targets for Autism Spectrum Disorder Treatment

Synthesis of Pharmaceutically Relevant 2‐Aminotetralin and 3‐Aminochroman Derivatives via Enzymatic Reductive Amination

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Product

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A new class of 5‐HT_2A/5‐HT_2C receptor inverse agonists: Synthesis, molecular modeling, in vitro and in vivo pharmacology of novel 2‐aminotetralins

A new class of 5‐HT_2A/5‐HT_2C receptor inverse agonists: Synthesis, molecular modeling, in vitro and in vivo pharmacology of novel 2‐aminotetralins