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Because α1-adrenergic receptor antagonists were found to block effects of adrafinil and modafinil in animals, "most investigators assume[d] that adrafinil and modafinil both serve as α1-adrenergic receptor agonists."[2] However, adrafinil and modafinil have not been found to bind to the α1-adrenergic receptor and they lack peripheral sympathomimetic side effects associated with activation of this receptor;[8] hence, the evidence in support of this hypothesis is weak, and other mechanisms are probable.[2] Modafinil was subsequently screened at a variety of targets in 2009 and was found to act as a weak, atypical blocker of the dopamine transporter (and hence as a dopamine reuptake inhibitor), and this action may explain some or all of its pharmacological effects.[9][10][11] Relative to adrafinil, modafinil possesses greater specificity in its action, lacking or having a reduced incidence of many of the common side effects of the former (including stomach pain, skin irritation, anxiety, and elevated liver enzymes with prolonged use).[12][13]

In 1976, two years after the discovery of adrafinil, modafinil, its active metabolite, was discovered.[14] Modafinil appeared to be more potent than adrafinil in animal studies, and was selected for further clinical development, with both adrafinil and modafinil eventually reaching the market.[14] Modafinil was first approved in France in 1994, and then in the United States in 1998.[15] Lafon was acquired by Cephalon in 2001.[16] As of September 2011, Cephalon has discontinued Olmifon, its adrafinil product, while modafinil continues to be marketed.[3]

In 2005 a Medical Classification Committee in New Zealand recommended to MEDSAFE NZ that adrafinil be classified as a prescription medicine due to risks of it being used as a party drug. At that time adrafinil was not scheduled in New Zealand.[18]

In a clinical trial with the tricyclic antidepressant clomipramine and placebo as comparators, adrafinil showed efficacy in the treatment of depression.[2] In contrast to clomipramine however, adrafinil was well-tolerated, and showed greater improvement in psychomotor retardation in comparison.[2] The authors concluded that further investigation of the potential antidepressant effects of adrafinil were warranted.[2]

Adrafinil is a synthetic psychostimulant agent and a prodrug of modafinil [CAS: 68693-11-8] that is a wakefulness-promoting agent used for treatment of disorders such as narcolepsy and shift work sleep disorder. The precise mechanisms of action are still unknown. Modafinil has weak to negligible interactions with receptors for norepinephrine, serotonin, dopamine, etc. Modafinil was widely believed to serve as a selective α1-adrenergic receptor agonist. Recent work, however, in vitro, modafinil binds to the dopamine transporter and inhibits dopamine reuptake. This activity has been associated in vivo with increased extracellular dopamine levels in some brain regions of animals. Adrafinil was sometimes used as a stimulatory agent in athletes, and were added to the prohibited list established by the World Anti-Doping Agency (WADA) in 2008. Therefore, the effective detection of adrafinil and its metabolites in human urine has been studied. (The product is for research purpose only.)ReferencesAdrafinil: a novel vigilance promoting agent (a review)N. W. Milgram, H. Callahan, C. Siwak, CNS Drug Rev. 1999, 5, 193.Adrafinil: effects on behavior and cognition in aged canines (a review)C. T. Siwak, H. Callahan, N. W. Milgram, Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2000, 24, 709.LC-ESI-MS determination and pharmacokinetics of adrafinil in ratsR. N. Rao, D. D. Shinde, M. V. N. K. Talluri, S. B. Agawane, J. Chromatogr. B 2008, 873, 119.Doping control analysis for adrafinil and its major metabolites in human urineJ. Lu, X. Wang, S. Yang, X. Liu, Y. Qin, L. Shen, Y. Wu, Y. Xu, M. Wu, G. Ouyang, Rapid Commun. Mass Spectrom. 2009, 23, 1592.Development of a validated LC method for enantiomeric separation and determination of adrafinil and its related substances on a Chiralcel OJ-H column connected to PDA and polarimetric detectors in seriesR. N. Rao, P. K. Maurya, D. D. Shinde, Biomed. Chromatogr. 2010, 24, 1228.Fluorescent zinc and copper complexes for detection of adrafinil in paper-based microfluidic devicesM. G. Caglayan, S. Sheykhi, L. Moscaa, P. Anzenbacher, Jr, Chem. Commun. 2016, 52, 8279.

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