Algorithmically designed peptides ameliorate behavioral defects in animal model of ADHD by an allosteric mechanism.
This study exemplifies the use of three ADHD-relevant methodological innovations. (1) The use of novel, patented, computational peptide design techniques to generate peptides targeting the extra-cellular and para-transmembrane amino acid loops of the putatively ADHD-involved, D(2) dopamine receptor, D(2)DAR; (2) experimental evidence that these peptides in L-amino acid/ortho ordered or D-amino acid/reverse ordered (retro-inverso), D(2)DAR, hydrophobic eigenmode matched forms, evoked positive allosteric and indirect agonist influences on in vitro stably receptor transfected CHO and LtK cells and on in vivo, brain mediated activity; (3) a representative 15 residue all-D-amino acid, D(2) mode matched peptide, given parenterally, was found to "repair" a key aberrant ADHD behavioral characteristic in a standard animal model of ADHD, the Spontaneously Hypertensive Rat, SHR, relative to its progenitor species control, the Wistar-Kyoto rat, WKY. The representative, retro-inverso peptide, all-D-LLYKNKPRYPKRNRE, reversed SHR's relative deficiency in sensory motor gating (pre-pulse inhibition, PPI) while leaving SHR's nonselective attention (rearings), impulsive behavior (time in center), and activity level (timed total motor behavior) unchanged. Amphetamine also reversed SHRs sensory gating defect, but with significant increases in nonselective attention, impulsivity and hyperactivity. These preliminary results suggest the possibility of a new, "softer" pharmacological approach to ADHD: hydrophobic mode matched peptide allosteric augmentation of the activity of indigenous dopamine with respect to D(2)DAR mediated function, in place of stimulant drug-induced presynaptic dopamine release or impairment of dopamine uptake.
Kinkead
Becky
B
Laboratory of Neuropsychopharmacology, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.
Selz
Karen A
KA
Owens
Michael J
MJ
Mandell
Arnold J
AJ
D000161:Acoustic Stimulation / Q000009:adverse effects; D000465:Algorithms; D000495:Allosteric Site / Q000187:drug effects; D000661:Amphetamine / Q000627:therapeutic use; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000150:complications / Q000188:drug therapy*; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000627:therapeutic use; D017076:Computer-Aided Design; D004195:Disease Models, Animal; D004298:Dopamine / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy* / Q000209:etiology; D009433:Neural Inhibition / Q000187:drug effects; D010455:Peptides / Q000737:chemistry* / Q000627:therapeutic use*; D051381:Rats; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000378:metabolism; D013216:Reflex, Startle / Q000502:physiology / Q000528:radiation effects; D013045:Species Specificity; D013997:Time Factors
D000697:Central Nervous System Stimulants; D004338:Drug Combinations; D008024:Ligands; D010455:Peptides; D017448:Receptors, Dopamine D2; D000661:Amphetamine; D004298:Dopamine