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1.
Nat Chem Biol ; 16(7): 749-755, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32483378

RESUMEN

Most drugs acting on G-protein-coupled receptors target the orthosteric binding pocket where the native hormone or neurotransmitter binds. There is much interest in finding allosteric ligands for these targets because they modulate physiologic signaling and promise to be more selective than orthosteric ligands. Here we describe a newly developed allosteric modulator of the ß2-adrenergic receptor (ß2AR), AS408, that binds to the membrane-facing surface of transmembrane segments 3 and 5, as revealed by X-ray crystallography. AS408 disrupts a water-mediated polar network involving E1223.41 and the backbone carbonyls of V2065.45 and S2075.46. The AS408 binding site is adjacent to a previously identified molecular switch for ß2AR activation formed by I3.40, P5.50 and F6.44. The structure reveals how AS408 stabilizes the inactive conformation of this switch, thereby acting as a negative allosteric modulator for agonists and positive allosteric modulator for inverse agonists.


Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/química , Antagonistas Adrenérgicos beta/química , Alprenolol/química , Norepinefrina/química , Receptores Adrenérgicos beta 2/química , Xinafoato de Salmeterol/química , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Antagonistas Adrenérgicos beta/farmacología , Regulación Alostérica , Sitio Alostérico , Alprenolol/farmacología , Células HEK293 , Humanos , Cinética , Ligandos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Norepinefrina/farmacología , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Estructura Secundaria de Proteína , Receptores Adrenérgicos beta 2/metabolismo , Xinafoato de Salmeterol/farmacología , Termodinámica , Agua/química
2.
J Med Chem ; 62(10): 5111-5131, 2019 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-31042379

RESUMEN

Starting from the ß-adrenoceptor agonist isoprenaline and beta-blocker carvedilol, we designed and synthesized three different chemotypes of agonist/antagonist hybrids. Investigations of ligand-mediated receptor activation using bioluminescence resonance energy transfer biosensors revealed a predominant effect of the aromatic head group on the intrinsic activity of our ligands, as ligands with a carvedilol head group were devoid of agonistic activity. Ligands composed of a catechol head group and an antagonist-like oxypropylene spacer possess significant intrinsic activity for the activation of Gαs, while they only show weak or even no ß-arrestin-2 recruitment at both ß1- and ß2-AR. Molecular dynamics simulations suggest that the difference in G protein efficacy and ß-arrestin recruitment of the hybrid ( S)-22, the full agonist epinephrine, and the ß2-selective, G protein-biased partial agonist salmeterol depends on specific hydrogen bonding between Ser5.46 and Asn6.55, and the aromatic head group of the ligands.


Asunto(s)
Agonistas Adrenérgicos beta/química , Antagonistas Adrenérgicos beta/química , Proteínas de Unión al GTP/efectos de los fármacos , Agonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Carvedilol/síntesis química , Carvedilol/química , Catecoles/química , Diseño de Fármacos , Humanos , Enlace de Hidrógeno , Indicadores y Reactivos , Isoproterenol/síntesis química , Isoproterenol/química , Ligandos , Ratones , Modelos Moleculares , Simulación de Dinámica Molecular , Xinafoato de Salmeterol/farmacología , beta-Arrestinas/efectos de los fármacos , beta-Arrestinas/metabolismo
3.
Bioorg Med Chem ; 24(12): 2641-53, 2016 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-27132867

RESUMEN

Aiming to discover dual-acting ß2 adrenergic/dopamine D2 receptor ligands, a structure-guided approach for the evolution of GPCR agonists that address multiple targets was elaborated. Starting from GPCR crystal structures, we describe the design, synthesis and biological investigation of a defined set of compounds leading to the identification of the benzoxazinone (R)-3, which shows agonist properties at the adrenergic ß2 receptor and substantial G protein-promoted activation at the D2 receptor. This directed approach yielded molecular probes with tuned dual activity. The congener desOH-3 devoid of the benzylic hydroxyl function was shown to be a ß2 adrenergic antagonist/D2 receptor agonist with Ki values in the low nanomolar range. The compounds may serve as a promising starting point for the investigation and treatment of neurological disorders.


Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/química , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Benzoxazinas/química , Benzoxazinas/farmacología , Agonistas de Dopamina/química , Agonistas de Dopamina/farmacología , Receptores de Dopamina D2/agonistas , Animales , Células CHO , Cricetulus , Descubrimiento de Drogas , Células HEK293 , Humanos , Modelos Moleculares , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Polifarmacología , Receptores Adrenérgicos beta 2/metabolismo , Receptores de Dopamina D2/metabolismo
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