title: 5,7-Dihydroxy-6-methoxy-4'-phenoxyflavone, a derivative of oroxylin A improves attention-deficit/hyperactivity disorder (ADHD)-like behaviors in spontaneously hypertensive rats.
abstract: Oroxylin A, a major flavonoid in Scutellaria baicalensis, has been shown to alleviate attention-deficit/hyperactivity disorder (ADHD)-like behaviors in the spontaneously hypertensive rat (SHR) model of ADHD. As part of our continuing effort to discover effective ADHD drug candidates, we synthesized a number of oroxylin A derivatives and characterized their biological activities. Among all oroxylin A analogs, compound 7-7 (5,7-dihydroxy-6-methoxy-4'-phenoxyflavone) showed the most remarkable inhibition of dopamine reuptake alike methylphenidate, a dopamine transporter (DAT) blocker and typical drug for ADHD, and oroxylin A. It did not influence norepinephrine reuptake unlike atomoxetine, a selective norepinephrine inhibitor. Moreover, compound 7-7 reduced hyperactivity, sustained inattention and impulsivity in the SHR as measured by the open field, Y-maze and electro-foot shock aversive water drinking tests, respectively. Most drugs that enhance brain dopamine levels (e.g. DAT blockers like cocaine and methylphenidate) produce behavioral effects like those of stimulants causing them to be abused. However, the repeated treatment of compound 7-7 failed to elicit locomotor sensitization in rats, and neither produced conditioned place preference response nor maintained self-administration behavior. Altogether, the present study suggests the promising therapeutic value of compound 7-7 as an ADHD drug. Furthermore, compound 7-7 may be considered as an alternative therapy to psychostimulant ADHD treatments (e.g. amphetamine and methylphenidate) for which use has been deemed controversial due to their abuse liability.
authors.affiliation: Uimyung Research Institute for Neuroscience, Sahmyook University, Seoul 139-742, Republic of Korea.
authors.forename: Ike C
authors.initials: IC
authors.lastname: dela Peña
authors.forename: Seo
authors.initials: S
authors.lastname: Young Yoon
authors.forename: Yeni
authors.initials: Y
authors.lastname: Kim
authors.forename: Haeil
authors.initials: H
authors.lastname: Park
authors.forename: Kyeong
authors.initials: K
authors.lastname: Man Kim
authors.forename: Jong
authors.initials: J
authors.lastname: Hoon Ryu
authors.forename: Chan
authors.initials: C
authors.lastname: Young Shin
authors.forename: Jae
authors.initials: J
authors.lastname: Hoon Cheong
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000378:metabolism; D001522:Behavior, Animal / Q000145:classification*; D001692:Biological Transport / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D047309:Flavones / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D005419:Flavonoids / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D013045:Species Specificity
chemical_list: C587699:5,7-dihydroxy-6-methoxy-4'-phenoxyflavone; D047309:Flavones; D005419:Flavonoids; C080669:5,7-dihydroxy-6-methoxy-2-phenylchromen-4-one; D004298:Dopamine
keywords: ADHD; Abuse potential; Oroxylin A derivative; SHR