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1.
J Med Chem ; 61(14): 6211-6235, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-29924931

RESUMO

A series of nipecotic acid derivatives with new azo benzene based photoswitchable N-substituents was synthesized and characterized in their ( E)- and ( Z)-form for their functional inhibitory activity at γ-aminobutyric acid transporters subtype 1 (GAT1), the most common γ-aminobutyric acid (GABA) transporter subtype in the central nervous system (CNS). This led to the identification of the first photoswitchable ligands exhibiting a moderate uptake inhibition of GABA in their ( E)- but distinctive higher inhibitory potency in their ( Z)-form resulting from photoirradiation. For the most efficient photoactivatable nipecotic acid derivative displaying an N-but-3-yn-1-yl linker with a terminal diphenyldiazene unit, an inhibitory potency of 4.65 ± 0.05 (pIC50) was found for its ( E)-form. which increased by almost two log units up to 6.38 ± 0.04 when irradiated. The effect of this photoswitchable mGAT1 inhibitor has also been evaluated and confirmed in patch-clamp recordings in acute hippocampal slices from mice.


Assuntos
Compostos Azo/química , Compostos Azo/farmacologia , Processos Fotoquímicos , Ácido gama-Aminobutírico/metabolismo , Transporte Biológico/efeitos dos fármacos , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , N-Acetilglucosaminiltransferases/antagonistas & inibidores , N-Acetilglucosaminiltransferases/química , N-Acetilglucosaminiltransferases/metabolismo , Ácidos Nipecóticos/química , Conformação Proteica , Relação Estrutura-Atividade
2.
ChemMedChem ; 12(5): 362-371, 2017 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-28125164

RESUMO

A new scaffold of highly potent and mGAT1-selective inhibitors has been developed. Compounds in this class are characterized by an alkyne-type spacer connecting nipecotic acid with an aromatic moiety. Preliminary evaluations made it apparent that a nipecotic acid derivative with an N-butynyl linker and a terminal 2-biphenyl residue exhibiting a binding affinity (pKi ) of 7.61±0.03 to mGAT1 and uptake inhibition (pIC50 ) of 7.00±0.06 selective for mGAT1 could serve as a hit compound. Docking calculations for compounds based on this structure in an hGAT1 homology modeling study indicated binding affinities similar to or even higher than that of the well-known mGAT1 inhibitor tiagabine. Synthesis of the designed compounds was readily carried out by two consecutive cross-coupling reactions, giving flexible access to variously substituted biphenyl subunits. With an appropriate substitution pattern of the biphenyl moiety, the binding affinity of enantiopure (R)-nipecotic acid derivatives to mGAT1 increased to pKi =8.33±0.01, and the uptake inhibitory potency up to pIC50 =7.72±0.02.


Assuntos
Proteínas da Membrana Plasmática de Transporte de GABA/química , Inibidores da Captação de GABA/química , Ácidos Nipecóticos/química , Sítios de Ligação , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Inibidores da Captação de GABA/síntese química , Inibidores da Captação de GABA/metabolismo , Células HEK293 , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Ácidos Nipecóticos/síntese química , Ácidos Nipecóticos/metabolismo , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
3.
J Med Chem ; 56(3): 1323-40, 2013 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-23336362

RESUMO

Mass spectrometric (MS) binding assays, a powerful tool to determine affinities of single drug candidates toward chosen targets, were recently demonstrated to be suitable for the screening of compound libraries generated with reactions of dynamic combinatorial chemistry when rendering libraries pseudostatic. Screening of small hydrazone libraries targeting γ-aminobutyric acid transporter 1 (GAT1), the most abundant γ-aminobutyric acid (GABA) transporter in the central nervous system, revealed two nipecotic acid derived binders with submicromolar affinities. Starting from the biphenyl carrying hit as lead structure, the objective of the present study was to discover novel high affinity GAT1 binders by screening of biphenyl focused pseudostatic hydrazone libraries formed from hydrazine 10 and 36 biphenylcarbaldehydes 11c-al. Hydrazone 12z that carried a 2',4'-dichlorobiphenyl residue was found to be the most potent binder with low nanomolar affinity (pK(i) = 8.094 ± 0.098). When stable carba analogues of representative hydrazones were synthesized and evaluated, the best binder 13z was again displaying the 2',4'-dichlorobiphenyl moiety (pK(i) = 6.930 ± 0.021).


Assuntos
Proteínas da Membrana Plasmática de Transporte de GABA/química , Hidrazonas/química , Espectrometria de Massas/métodos , Hidrazonas/síntese química
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