Inhibitory and facilitory actions of isocyanine derivatives at human and rat organic cation transporters 1, 2 and 3: a comparison to human alpha 1- and alpha 2-adrenoceptor subtypes.
Organic cation transporters (OCTs), comprising OCT1, OCT2 and OCT3 subtypes, control absorption and elimination of xenobiotics and endogenous compounds in kidney, liver and placenta. In addition, they ensure "uptake2", low-affinity catecholamine clearance in sympathetically-innervated tissue and the CNS. The prototypical OCT ligand, disprocynium24 (D24), recognises OCT3, but its actions at OCT1 and OCT2 remain unknown. Herein, together with two other isocyanine derivatives (AAC291 and AAC301) and chemically-related adrenergic agents, we evaluated actions of D24 at OCTs, monoamine transporters and alpha(1)- and alpha(2)-adrenoceptors. D24 concentration-dependently suppressed [3H]-1-methyl-4-phenylpyridinium (MPP+) transport at human (h) and rat (r) OCT1, OCT2 and OCT3 in stably transfected HEK293 cells. Interestingly, low concentrations of D24 enhanced transport by h/rOCT2, a substrate-dependent effect suppressed by inhibition of protein kinase C. AAC291 and AAC301 likewise inhibited transport by all classes of h/r OCT and at low concentrations induced even more marked increases in transport by h/rOCT2. Further, by analogy to D24, they displayed antagonist properties at halpha(1A/B/D)-adrenoceptors (Ca2+-flux) and halpha(2A/B/C)-adrenoceptors ([35S]GTPgammaS binding). They were, however, less potent than D24 at serotonin transporters ([3H]citalopram binding) and AAC291 did not bind to dopamine and norepinephrine transporters. The preferential alpha(1B)-adrenoceptor antagonist, AH11110A, the alpha2-adrenoceptor agonist, RWJ52353, and the adrenergic neurotoxin DSP-4 likewise affected [3H]MPP+ transport, in an OCT-subtype and species-dependent manner. In conclusion, D24, other isocyanine congeners and chemically-related adrenergic agents inhibit OCT-mediated [3H]MPP+ transport, and all drugs display significant activity at alpha1- and alpha2-adrenoceptor subtypes, expanding previous reports of promiscuity between pharmacophores recognising alpha-adrenoceptors and OCTs.
Amphoux
Anne
A
INSERM U952, 75005, Paris, France.
Millan
Mark J
MJ
Cordi
Alex
A
Bönisch
Heinz
H
Vialou
Vincent
V
Mannoury la Cour
Clotilde
C
Dupuis
Delphine S
DS
Giros
Bruno
B
Gautron
Sophie
S
D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000378:metabolism / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D029362:Organic Anion Transporters, Sodium-Independent / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011804:Quinolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D013045:Species Specificity
D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D029362:Organic Anion Transporters, Sodium-Independent; D027702:Organic Cation Transporter 1; D011804:Quinolines; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; C490280:SLC22A7 protein, human; C114338:organic anion transport protein 3; C103851:disprocynium 24