RESEARCH MONOGRAPH · KDC-MN-259
Guanfacine
Guanfacine is a more selective cousin of clonidine, originally a blood-pressure drug (Tenex) that found a second life as a non-stimulant ADHD medication (Intuniv, extended-release form). Where clonidine hits all three alpha-2 receptor subtypes broadly, guanfacine prefers the alpha-2A subtype, which is concentrated in the prefrontal cortex (the executive-function part of the brain). Activating it there appears to strengthen working memory and reduce impulsivity, which is the rationale for ADHD use. It is less sedating than clonidine at equivalent effect and is FDA-approved for ADHD in children and adolescents. Often combined with stimulants when stimulants alone are insufficient. Not stocked by Kodiac. This monograph is provided for research and educational reference.
Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.
Selective alpha-2A adrenergic agonist
A selective alpha-2A adrenergic agonist; an antihypertensive repurposed as a non-stimulant ADHD treatment with greater alpha-2A selectivity than clonidine.
Abstract
Guanfacine (N-{[2-(2,6-dichlorophenyl)acetyl]amino}guanidine; CAS 29110-47-2; molecular formula C9H9Cl2N3O; molecular weight 246.10) is a selective alpha-2A adrenergic agonist developed at Sandoz in the 1970s and approved by the FDA in 1986 under the trade name Tenex (immediate release) and 2009 as Intuniv (extended release for ADHD). Distinct from clonidine by greater alpha-2A subtype selectivity (approximately 25-fold over alpha-2B and alpha-2C); the alpha-2A subtype predominates in the prefrontal cortex where it modulates working memory and executive function, supporting the cognitive enhancement seen in ADHD. The CNS-prefrontal cortex effect is more pronounced than the cardiovascular effect at clinical ADHD doses. Plasma half-life is approximately 17 hours, supporting dosing in published studies in the ER formulation. Renal excretion is the principal clearance pathway. Approved for hypertension and (Intuniv) ADHD in children and adolescents. Used as the canonical alpha-2A selective agonist in prefrontal cortex pharmacology and ADHD research.
Mechanism of action
Selective alpha-2A adrenergic agonism (~25-fold over 2B/2C). Prefrontal cortex effects on working memory and executive function.
Reported research dose ranges
Clinical 1 to 4 mg in the published literature (ADHD); 1 to 3 mg in the published literature (hypertension). Rodent studies 0.05 to 1 mg/kg.
References
- Arnsten AF. The use of alpha-2A adrenergic agonists for the treatment of attention-deficit/hyperactivity disorder. Expert Rev Neurother 2010.
- Sallee FR, et al. Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2009.
- Wang M, et al. Alpha-2A adrenoceptor stimulation strengthens working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 2007.
Read the full monograph
The full reference document is available as a research-use-only PDF download. Note: PDFs for newly added compounds may take a few hours to propagate after this article was published.
The full reference document is provided strictly for research use only. It reports research dose ranges from the published literature, not instructions for use in humans or animals.
FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.