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1.
Biochem Pharmacol ; 171: 113731, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31783011

RESUMO

Stereoselectivity is well described for receptor binding and enzyme catalysis, but so far has only been scarcely investigated in carrier-mediated membrane transport. We thus studied transport kinetics of racemic (anti)adrenergic drugs by the organic cation transporters OCT1 (wild-type and allelic variants), OCT2, OCT3, MATE1, and MATE2-K with a focus on stereospecificity. OCT1 showed stereoselective uptake with up to 2-fold higher vmax over their corresponding counterpart enantiomers for (R,R)-fenoterol, (R,R)-formoterol, (S)-salbutamol, (S)-acebutolol, and (S)-atenolol. Orciprenaline and etilefrine were also transported stereoselectively. The Km was 2.1-fold and 1.5-fold lower for the (S,S)-enantiomers of fenoterol and formoterol, while no significant difference in Km was seen for the other aforementioned drugs. Common OCT1 variants showed similar enantiopreference to wild-type OCT1, with a few notable exceptions (e.g. a switch in enantiospecificity for fenoterol in OCT1*2 compared to the wild-type). Other cation transporters showed strong differences to OCT1 in stereoselectivity and transport activity: The closely related OCT2 displayed a 20-fold higher vmax for (S,S)-fenoterol compared to (R,R)-fenoterol and OCT2 and OCT3 showed 3.5-fold and 4.6-fold higher vmax for the pharmacologically active (R)-salbutamol over (S)-salbutamol. MATE1 and MATE2-K generally mediated transport with a higher capacity but lower affinity compared to OCT1, with moderate stereoselectivity. Our kinetic studies showed that significant stereoselectivity exists in solute carrier-mediated membrane transport of racemic beta-adrenergic drugs with surprising, and in some instances even opposing, preferences between closely related organic cation transporters. This may be relevant for drug therapy, given the strong involvement of these transporters in hepatic and renal drug elimination.


Assuntos
Agonistas Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/farmacologia , Proteínas de Transporte de Cátions Orgânicos/agonistas , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Acebutolol/química , Acebutolol/metabolismo , Acebutolol/farmacologia , Agonistas Adrenérgicos/química , Agonistas Adrenérgicos/metabolismo , Antagonistas Adrenérgicos/química , Antagonistas Adrenérgicos/metabolismo , Atenolol/química , Atenolol/farmacologia , Transporte Biológico , Fenoterol/química , Fenoterol/metabolismo , Fenoterol/farmacologia , Fumarato de Formoterol/química , Fumarato de Formoterol/metabolismo , Fumarato de Formoterol/farmacologia , Células HEK293 , Humanos , Cinética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 1 de Cátions Orgânicos/agonistas , Transportador 1 de Cátions Orgânicos/antagonistas & inibidores , Transportador 1 de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico/agonistas , Transportador 2 de Cátion Orgânico/antagonistas & inibidores , Transportador 2 de Cátion Orgânico/metabolismo , Estereoisomerismo
2.
Eur J Pharmacol ; 634(1-3): 1-9, 2010 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-20170649

RESUMO

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.


Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Transportador 1 de Cátions Orgânicos/metabolismo , Quinolinas/química , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Agonistas de Receptores Adrenérgicos alfa 1 , Antagonistas de Receptores Adrenérgicos alfa 1 , Agonistas de Receptores Adrenérgicos alfa 2 , Antagonistas de Receptores Adrenérgicos alfa 2 , Agonistas alfa-Adrenérgicos/metabolismo , Antagonistas Adrenérgicos alfa/metabolismo , Animais , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Masculino , Transportadores de Ânions Orgânicos Sódio-Independentes/agonistas , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Transportador 1 de Cátions Orgânicos/agonistas , Transportador 1 de Cátions Orgânicos/antagonistas & inibidores , Quinolinas/metabolismo , Quinolinas/farmacologia , Ratos , Ratos Wistar , Especificidade da Espécie
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