Dataset Information

Development of 2-Aminotetralin-Type Serotonin 5-HT₁ Agonists: Molecular Determinants for Selective Binding and Signaling at 5-HT_1A, 5-HT_1B, 5-HT_1D, and 5-HT_1F Receptors.

ABSTRACT: The serotonin (5-hydroxytryptamine, 5-HT) 5-HT₁ G-protein coupled receptor subtypes (5-HT_{1A/1B/1D/1E/1F}) share a high sequence homology, confounding development of subtype-specific ligands. This study used a 5-HT₁ structure-based ligand design approach to develop subtype-selective ligands using a 5-substituted-2-aminotetralin (5-SAT) chemotype, leveraging results from pharmacological, molecular modeling, and mutagenesis studies to delineate molecular determinants for 5-SAT binding and function at 5-HT₁ subtypes. 5-SATs demonstrated high affinity (K_i ≤ 25 nM) and at least 50-fold stereoselective preference ([2S] > [2R]) at 5-HT_1A, 5-HT_1B, and 5-HT_1D receptors but essentially nil affinity (K_i > 1 μM) at 5-HT_1F receptors. The 5-SATs tested were agonists with varying degrees of potency and efficacy, depending on chemotype substitution and 5-HT₁ receptor subtype. Models were built from the 5-HT_1A (cryo-EM), 5-HT_1B (crystal), and 5-HT_1D (cryo-EM) structures, and 5-SATs underwent docking studies with up to 1 μs molecular dynamics simulations. 5-SAT interactions observed at positions 3.33, 5.38, 5.42, 5.43, and 7.39 of 5-HT₁ subtypes were confirmed with point mutation experiments. Additional 5-SATs were designed and synthesized to exploit experimental and computational results, yielding a new full efficacy 5-HT_1A agonist with 100-fold selectivity over 5-HT_1B/1D receptors. The results presented lay the foundation for the development of additional 5-HT₁ subtype selective ligands for drug discovery purposes.

SUBMITTER: McGlynn RP

PROVIDER: S-EPMC10797628 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Development of 2-Aminotetralin-Type Serotonin 5-HT1 Agonists: Molecular Determinants for Selective Binding and Signaling at 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT1F Receptors.

McGlynn Ryan P RP Cui Meng M Brems Brittany B Holbrook Otto O Booth Raymond G RG

ACS chemical neuroscience 20231227 2

The serotonin (5-hydroxytryptamine, 5-HT) 5-HT1 G-protein coupled receptor subtypes (5-HT1A/1B/1D/1E/1F) share a high sequence homology, confounding development of subtype-specific ligands. This study used a 5-HT1 structure-based ligand design approach to develop subtype-selective ligands using a 5-substituted-2-aminotetralin (5-SAT) chemotype, leveraging results from pharmacological, molecular modeling, and mutagenesis studies to delineate molecular determinants ...[more]

PMID: 38150333

Similar Datasets

Project description:Serotoninergic (5-HT) neurons are powerful modulators of spinal locomotor circuits. Most studies on 5-HT modulation focused on the effect of exogenous 5-HT and these studies provided key information about the cellular mechanisms involved. Less is known about the effects of increased release of endogenous 5-HT with selective serotonin reuptake inhibitors. In mammals, such molecules were shown to destabilize the fictive locomotor output of spinal limb networks through 5-HT1A receptors. However, in tetrapods little is known about the effects of increased 5-HT release on the locomotor output of axial networks, which are coordinated with limb circuits during locomotion from basal vertebrates to mammals. Here, we examined the effect of citalopram on fictive locomotion generated in axial segments of isolated spinal cords in salamanders, a tetrapod where raphe 5-HT reticulospinal neurons and intraspinal 5-HT neurons are present as in other vertebrates. Using electrophysiological recordings of ventral roots, we show that fictive locomotion generated by bath-applied glutamatergic agonists is destabilized by citalopram. Citalopram-induced destabilization was prevented by a 5-HT1A receptor antagonist, whereas a 5-HT1A receptor agonist destabilized fictive locomotion. Using immunofluorescence experiments, we found 5-HT-positive fibers and varicosities in proximity with motoneurons and glutamatergic interneurons that are likely involved in rhythmogenesis. Our results show that increasing 5-HT release has a deleterious effect on axial locomotor activity through 5-HT1A receptors. This is consistent with studies in limb networks of turtle and mouse, suggesting that this part of the complex 5-HT modulation of spinal locomotor circuits is common to limb and axial networks in limbed vertebrates.NEW & NOTEWORTHY Little is known about the modulation exerted by endogenous serotonin on axial locomotor circuits in tetrapods. Using axial ventral root recordings in salamanders, we found that a serotonin reuptake blocker destabilized fictive locomotor activity through 5-HT1A receptors. Our anatomical results suggest that serotonin is released on motoneurons and glutamatergic interneurons possibly involved in rhythmogenesis. Our study suggests that common serotoninergic mechanisms modulate axial motor circuits in amphibians and limb motor circuits in reptiles and mammals.

Dataset Information

Development of 2-Aminotetralin-Type Serotonin 5-HT₁ Agonists: Molecular Determinants for Selective Binding and Signaling at 5-HT_1A, 5-HT_1B, 5-HT_1D, and 5-HT_1F Receptors.

Publications

Development of 2-Aminotetralin-Type Serotonin 5-HT<sub>1</sub> Agonists: Molecular Determinants for Selective Binding and Signaling at 5-HT<sub>1A</sub>, 5-HT<sub>1B</sub>, 5-HT<sub>1D</sub>, and 5-HT<sub>1F</sub> Receptors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets