Stability of interactions between PUT and CAD and human TAAR6 and TAAR8.

<p>Time evolution (x-axis) of intermolecular distances (y-axis) between Asp_3.32/5.43 (-COO^-) and PUT/CAD (-NH3⁺) in 1.0 μs unbiased MD simulations. Each plot corresponds to one of the eight simulated ligand-receptor molecular complexes: hTAAR6_active-like/PUT (A), hTAAR6_active-like/CAD (B), hTAAR8_active-like/PUT (C), hTAAR8_active-like/CAD (D), hTAAR6_{inactive-like}/PUT (E), hTAAR6_{inactive-like}/CAD (F), hTAAR8_{inactive-like}/PUT (G), hTAAR8_{inactive-like}/CAD (H). Continuous and dotted lines correspond to distances between N1 and N2 atoms of the ligands with Asp_3.32 (red) and Asp_5.43 (blue) carboxyl groups, respectively. Black arrows at the bottom indicate the flip-transitions (180° rotation) of PUT and CAD in the binding pocket of the inactive-like models.</p

Multiple sequence alignment of representative aminergic receptors and selected TAARs from different organisms.

<p>Positions that are at least 30% or 95% conserved are highlighted in gray and black, respectively. Highly conserved residues in the class A GPCR family are indicated by the Ballesteros-Weinstein numbering (X.50 of helix X), as well as the conserved cysteines involved in disulfide bridges (in yellow). Residues at position 3.32 and 5.42/5.43 are highlighted in red. Non-conserved N-, C- terminal and ICL3 amino acid sequences are omitted from the figure. <i>Acronyms</i>: h5HT1B (human 5-hydroxytryptamine receptor 1B), hH1R (human histamine receptor H1), hD3R (human dopamine receptor D3), hADRB2 (human β₂-adrenergic receptor), hTAAR6 (human trace-amine associated receptor 6), hTAAR8 (human trace-amine associated receptor 8), mTAAR6 (mouse trace-amine associated receptor 6), mTAAR8b (mouse trace-amine associated receptor 8b), rTAAR6 (rat trace-amine associated receptor 6), rTAAR8a (rat trace-amine associated receptor 8a), zTAAR13c (zebrafish trace-amine associated receptor 13c) and zTAAR13d (zebrafish trace-amine associated receptor 13d).</p

The orthosteric ligand-binding pocket of human TAAR6 and TAAR8.

<p>Surface representation of the molecular models of hTAAR6 (A and C) and hTAAR8 (B and D) in the active- (top panels) and inactive-like (bottom panels) conformations. Extracellular view of the identified ligand binding cavities with molecular surfaces colored by the electrostatic potential calculated using the program APBS with nonlinear Poisson-Boltzmann equation and contoured at ±10 kT/e (negatively and positively charged surface areas in red and blue, respectively). Residues contributing to the electronegative potential of the binding pocket are represented in sticks and numbered according to the receptor type (Ballesteros-Weinstein scheme in parenthesis). Calculated distances between carboxyl moieties of Asp_3.32 and Asp_5.43 are shown for each molecular structure (yellow dashed lines). Protein backbones are shown in cylinders except ECL2 conformations (here omitted for clarity).</p

Molecular interactions of PUT and CAD with human TAAR6 and TAAR8.

<p>(A) Key features of the full agonist adrenaline (ADR, blue sticks) in the binding pocket of the ADRB2 active structure (PDB ID:4LDO; region comprising the TMs 3-5-6-7 in green ribbons). (B) Superposition of molecular docking of putrescine (PUT, yellow sticks), and (C) cadaverine (CAD, orange sticks), in the active-like TAAR6 (light-gray ribbons) and TAAR8 (light-blue ribbons) molecular models. Contact residues at a distance < 3.5 Å from ligands are shown in sticks and numbered according to Ballesteros-Weinstein numbering. Predicted (ligand–receptor) hydrogen bonds and salt bridge interactions are shown in dashed lines. The 2D chemical structure of PUT and CAD protonated at physiological pH, with estimated pKa1 and pKa2 for each amino group are indicated at the bottom of panels B and C, respectively.</p

Cladogram representing the presence of TAARs in a consensus phylogeny of different vertebrates.

<p>The total number of functional TAAR genes is shown in parenthesis for each organism. Teleost TAAR13c/TAAR13d with proven affinity for CAD/PUT, respectively and therian-specific TAAR6/TAAR8 with the conserved tandem of aspartates in the TM3 and TM5 appear in bold (corresponding to black silhouettes in the species of origin). Approximate divergence times between species (million years ago; MYA) are shown in the internal nodes.</p

Effect of PUT and CAD on the ‘transmission switch’ amino acids.

<p>(A) Structural attributes of the ‘transmission switch’ residues 3.40, 5.50 and 6.44 (in sticks), in TMs 3-5-6 (in cylinders), on the ADRB2 in agonist bound active- (PDB ID: 3SN6, in green) and inverse agonist bound inactive- conformation (2RH1, in red). Arrows represent the observed movement of the helices in the transition from the inactive to the active state of the receptor. (B) Distribution of L_3.40, P_5.50 and F_6.44 Cβ atoms positions (dots) in the TAAR6 and (C) V_3.40, P_5.50 and F_6.44 Cβ atoms in the TAAR8 during simulations of active-like PUT/CAD bound in green/light green and inactive-like PUT/CAD bound in red/light red. Numbers correspond to the standard deviation (SD) of the Cβ atoms positions from the centroid of 100 evenly spaced snapshots extracted from the 1.0 μs of unbiased MD simulations.</p

Serotonin 5‑HT₆ Receptor Antagonists for the Treatment of Cognitive Deficiency in Alzheimer’s Disease

Alzheimer’s disease (AD) is one of the most frequent causes of death and disability worldwide and has a significant clinical and socioeconomic impact. In the search for novel therapeutic strategies, serotonin 5-HT₆ receptor (5-HT₆R) has been proposed as a promising drug target for cognition enhancement in AD. This manuscript reviews the compelling evidence for the implication of this receptor in learning and memory processes. We have summarized the current status of the medicinal chemistry of 5-HT₆R antagonists and the encouraging preclinical findings that demonstrate their significant procognitive behavioral effects in a number of learning paradigms, probably acting through modulation of multiple neurotransmitter systems and signaling pathways. The results of the ongoing clinical trials are eagerly awaited to shed some light on the validation of 5-HT₆R antagonists as a new drug class for the treatment of symptomatic cognitive impairment in AD, either as stand-alone therapy or in combination with established agents

The Extracellular Entrance Provides Selectivity to Serotonin 5‑HT₇ Receptor Antagonists with Antidepressant-like Behavior in Vivo

The finding that ergotamine binds serotonin receptors in a less conserved extended binding pocket close to the extracellular entrance, in addition to the orthosteric site, allowed us to obtain 5-HT₇R antagonist <b>6</b> endowed with high affinity (<i>K</i>_i = 0.7 nM) and significant 5-HT_1AR selectivity (ratio >1428). Compound <b>6</b> exhibits in vivo antidepressant-like effect (1 mg/kg, ip) mediated by the 5-HT₇R, which reveals its interest as a putative research tool or pharmaceutical in depression disorders

Modulation of the Interaction between a Peptide Ligand and a G Protein-Coupled Receptor by Halogen Atoms

Systematic halogenation of two native opioid peptides has shown that halogen atoms can modulate peptide–receptor interactions in different manners. First, halogens may produce a steric hindrance that reduces the binding of the peptide to the receptor. Second, chlorine, bromine, or iodine may improve peptide binding if their positive σ-hole forms a halogen bond interaction with negatively charged atoms of the protein. Lastly, the negative electrostatic potential of fluorine can interact with positively charged atoms of the protein to improve peptide binding

Additional file 2: of Cross-communication between Gi and Gs in a G-protein-coupled receptor heterotetramer guided by a receptor C-terminal domain

Table S1. List of target sequences and template structures used to construct the computer models of A1-A2AHet in complex with Gi and Gs. (PDF 23 kb