Guanfacine Hydrochloride (CAS 29110-48-3) is the hydrochloride salt of guanfacine, a selective α2A-adrenoceptor agonist with a Kd of roughly 31 nM and about 60-fold selectivity over α2B. It is the active ingredient in the antihypertensive Tenex and the extended-release ADHD medication Intuniv. Researchers use it to model prefrontal cognition, ADHD, noradrenergic signalling, autonomic control and trauma-related nightmares because its α2A preference gives clean PFC effects with far less sedation than the non-selective α2 agonist clonidine.

Both are centrally acting α2 agonists, but guanfacine is markedly α2A-selective (~60-fold over α2B, ~40-fold over α2C), whereas clonidine engages all α2 subtypes and imidazoline I1 receptors. Guanfacine therefore delivers stronger prefrontal cognitive enhancement with less sedation, hypotension and bradycardia — which is why it is the preferred α2A probe in cognition and ADHD research. Clonidine remains useful where broad α2/imidazoline activity is desired.

Postsynaptic α2A adrenoceptors in the prefrontal cortex are the subtype that strengthens PFC network connectivity, dendritic-spine density and signal-to-noise processing. Guanfacine's α2A preference recruits exactly this pro-cognitive circuit while largely sparing α2B/α2C subtypes (vasoconstriction, sedation). This selectivity is the mechanistic basis for its use as a prefrontal cognition-enhancing research tool.

Guanfacine binds postsynaptic α2A receptors on PFC pyramidal neurons, coupling via Gi/o to inhibit adenylyl cyclase, lower cAMP and reduce hyperpolarization-activated (HCN) channel current (Ih). Membrane stabilization strengthens recurrent PFC connections, increases dendritic-spine density and improves the signal-to-noise ratio of cortical processing — translating into better working memory, attention and impulse control in experimental models.

Intuniv is the brand name for guanfacine extended-release, a once-daily formulation approved for pediatric ADHD. Tenex is the immediate-release form used for hypertension. Both contain guanfacine as the active moiety; the extended-release version sustains plasma levels to support daytime executive-function control. In research, guanfacine HCl powder is formulated by the investigator for the required route and release profile.

Guanfacine HCl is freely soluble in water (at least ~28 mg/mL, ~100 mM) and also in DMSO (~28 mg/mL). Prepare aqueous or DMSO stock solutions as needed; the hydrochloride salt dissolves readily at room temperature. Store the solid at room temperature (15-25°C), desiccated and protected from light. Aqueous and DMSO stocks are stable for weeks at 4 °C; for long-term storage keep aliquots at -20 °C and avoid repeated freeze-thaw cycles.

In biochemical assays (binding/cAMP), guanfacine is used in the low nanomolar to micromolar range (Kd ~31 nM; functional EC50s typically tens to hundreds of nM depending on readout). In rodent studies, published doses commonly span ~0.1-3 mg/kg by intraperitoneal or oral gavage; the extended-release clinical equivalent is ~1-4 mg/day in humans. Always run a dose-response and include a vehicle-matched control, and confirm target engagement with a cAMP or electrophysiological readout.

Best practice is to (1) include a vehicle-only control at matched concentration; (2) confirm α2A engagement via a cAMP accumulation or radioligand-binding assay; (3) compare against a structurally distinct α2A agonist (e.g., clonidine or dexmedetomidine) and, where useful, an α2A antagonist (e.g., atipamezole, yohimbine); and (4) verify PFC-specific effects with electrophysiology or dendritic-spine imaging rather than relying on behaviour alone.

Yes. α2A agonism produces analgesia through spinal and supraspinal noradrenergic pathways, so guanfacine is studied as an opioid-sparing analgesic adjuvant. Separately, its κ-receptor-sparing α2A profile is investigated for reducing trauma-associated nightmares and improving sleep in PTSD models — a distinct, well-cited repurposing application beyond its ADHD and cardiovascular uses.

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