ADRA2A

Alpha-2A adrenergic receptor

Score: 0.676 Price: $0.68 Medium Druggability Status: active Wiki: ADRA2A

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

DEBATES

3D Protein Structure

🧬 ADRA2A — PDB 6KUX Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Medium

Score: 0.59

Clinical Stage

Approved

Target Class

Gpcr

Safety

0.60

Druggability Analysis

Drug Development0.90

Structural Tractability0.85

Target Class0.85

Safety Profile0.60

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (2 compounds)

2 Approved

Therapeutic Areas:

Cognitive dysfunction in Parkinson's disease Attention deficit and arousal disorders Neurodegenerative disease-associated delirium Stress-related neuropsychiatric conditions Age-related cognitive decline Noradrenergic system restoration in neurodegeneration

Druggability Rationale: ADRA2A demonstrates exceptional druggability with a score of 0.90, supported by 18 PDB structures at high resolution (2.7 Å best), robust GPCR precedent with approved drugs (dexmedetomidine, clonidine), and well-characterized orthosteric binding pockets. The established clinical validation through phase 4 trials and multiple structural modalities (X-ray crystallography, AlphaFold, cryo-EM) provide comprehensive chemical matter and design frameworks for rational drug development.

Mechanism: Small molecule agonists and antagonists modulating noradrenergic signaling

Drug Pipeline (2 compounds)

2 Approved

Known Drugs:

Dexmedetomidine (approved) — Sedation, delirium prevention

Clonidine (approved) — Various CNS applications

Structural Data:

PDB (18) ✓AlphaFold ✓Cryo-EM ✓

1HLL 1HO9 1HOD 1HOF 6K41+13 more

UniProt: P08913

Binding Pocket Analysis:

The orthosteric binding pocket is well-characterized across 18 crystal structures, accommodating small lipophilic ligands with high affinity through conserved residues in transmembrane helices 3, 5, and 6. Structural data reveals allosteric modulation potential at intracellular G-protein coupling interfaces, providing opportunities for biased signaling approaches beyond classical agonist/antagonist pharmacology.

🧬 3D Protein Structure

🧬 ADRA2A — PDB 6KUX Click to expand interactive 3D viewer

Experimental structure from RCSB PDB | Powered by Mol* | Rotate: click+drag | Zoom: scroll

Selectivity & Safety Considerations

ADRA2A selectivity poses a moderate challenge due to high sequence homology with ADRA2B and ADRA2C isoforms; however, existing approved drugs demonstrate achievable selectivity windows. Off-target CNS effects (hypotension, sedation) and peripheral adrenergic activity remain key liabilities requiring structure-based design to minimize cross-reactivity with other GPCR subtypes.