Adenosine A2a Receptor Puns

We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X‐ray crystallography to reveal the binding mode of an antagonist series to the adenosine A 2A receptor (AR). Eight A 2A AR binding site mutations from biophysical mapping experiments were initially analysed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives. Their affinities for the A 2A AR were experimentally determined and investigated through a cycle of ligand‐FEP calculations, validating the binding orientation of the different chemical substituents proposed. Subsequent X‐ray crystallography of the A2AAR with a low and a high affinity chromone derivative confirmed the predicted binding orientation. The new molecules and structures here reported were driven by free energy calculations, and provide new insights on antagonist binding to the A 2A AR, an emerging target in immuno‐oncology.

https://ift.tt/37CGvG9

I found this study on this website, quoting:

>A 2014 study looked at squirrel monkeys who had been given THC, the compound in marijuana that produces the high. The monkeys had the option to keep receiving more THC.
>
>Researchers then gave them different doses of MSX-3, which produces effects similar to those of caffeine. When given low doses of MSX-3, the monkeys gave themselves less THC. But at high doses, the monkeys gave themselves more THC.
>
>This suggests that low levels of caffeine may enhance your high so you don’t use as much. But high levels of caffeine could affect your high in the opposite way, leading you to use more marijuana.
>
>More research as needed, as this small study was conducted only on animals, not humans.

What's your opinion? Anyone knows any other study similar to this one?
I "empirically" noticed that when I'm tired and partially sleep-deprived, weed gets me higher but I thought it was a bias due to fatigue, such as need for sleep tends to make you sleepier, and being sleepy is similar to being high but not quite the same. Btw, sometimes I noticed that an evening short nap can affect high as well.
Seems like there might actually be some kind of correlation between sleep and weed high?

http://www.ncbi.nlm.nih.gov/pubmed/25772255

Abstract
Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial remodeling mainly due to excess cellular proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs). Salidroside, an active ingredient isolated from Rhodiola rosea is proposed to exert protective effects against PAH. However, the function of salidroside in PAH has not been investigated systematically and the underlying mechanisms are not clear. To investigate the effects of salidroside on PAH, the mice in chronic hypoxia model of PAH were given by an increasing concentration of salidroside (0, 16mg/kg, 32mg/kg, and 64mg/kg). After salidroside treatment, the chronic hypoxia-induced right ventricular hypertrophy and pulmonary arterial remodeling were attenuated, suggesting a protective role played by salidroside in PAH. To explore the potential mechanisms, the apoptosis of PASMCs after salidroside treatment under hypoxia conditions were determined in vivo and in vitro, and also the mitochondria-dependent apoptosis factors, Bax, Bcl-2, cytochrome C, and caspase 9 were examined. The results revealed that salidroside reversed hypoxia-induced cell apoptosis resistance at least partially via a mitochondria-dependent pathway. In addition, salidroside upregulated the expression of adenosine A2a receptor (A2aR) in lung tissues of mice and in PASMCs in vitro after hypoxia exposure. Combined the evidence above, we conclude that salidroside can attenuate chronic hypoxia-induced PAH by promoting PASMCs apoptosis via an A2aR related mitochondria dependent pathway.

In molecular design , structural, pharmacological and chemical information can be interconnected by computational estimations of binding free energies. Using a combined FEP approach to examine both mutagenesis and ligand SAR, we designed new analogues of the A2AAR antagonist series of chromones. Subsequent crystal structures supported the rational design of these compounds, linking the structural and energetic understanding on ligand binding.

Abstract

We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X‐ray crystallography to reveal the binding mode of an antagonist series to the A2A adenosine receptor (AR). Eight A2AAR binding site mutations from biophysical mapping experiments were initially analyzed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives. Their affinities for the A2AAR were experimentally determined and investigated through a cycle of ligand‐FEP calculations, validating the binding orientation of the different chemical substituents proposed. Subsequent X‐ray crystallography of the A2AAR with a low and a high affinity chromone derivative confirmed the predicted binding orientation. The new molecules and structures here reported were driven by free energy calculations, and provide new insights on antagonist binding to the A2AAR, an emerging target in immuno‐oncology.

https://ift.tt/37CGvG9

In molecular design, structural, pharmacological and chemical information can be interconnected by computational estimations of binding free energies. Using a combined FEP approach to examine both mutagenesis and ligand SAR, we designed new analogues of the A2AAR antagonist series of chromones. Subsequent crystal structures supported the rational design of these compounds, linking the structural and energetic understanding on ligand binding.

Abstract

We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X‐ray crystallography to reveal the binding mode of an antagonist series to the A2A adenosine receptor (AR). Eight A2AAR binding site mutations from biophysical mapping experiments were initially analyzed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives. Their affinities for the A2AAR were experimentally determined and investigated through a cycle of ligand‐FEP calculations, validating the binding orientation of the different chemical substituents proposed. Subsequent X‐ray crystallography of the A2AAR with a low and a high affinity chromone derivative confirmed the predicted binding orientation. The new molecules and structures here reported were driven by free energy calculations, and provide new insights on antagonist binding to the A2AAR, an emerging target in immuno‐oncology.

https://ift.tt/37CGvG9