RESUMEN
The various physiological actions of the neurohormone melatonin are mediated mainly by two G-protein-coupled MT(1) and MT(2) receptors. The melatoninergic drugs on the market, ramelteon and agomelatine, as well as the most advanced drug candidates under clinical evaluation, tasimelteon and PD-6735, are high-affinity nonselective MT(1) and MT(2) agonists. However, exploring the exact physiological role of the MT(1) and MT(2) melatonin receptors requires subtype selective MT(1) and MT(2) ligands. This review covers novel melatoninergic agonists and antagonists published since 2010, focusing on high-affinity and subtype selective agents. Additionally, compounds not mentioned in the previous review articles and ligands selective for the MT(3) binding site are included.
Asunto(s)
Acetamidas/farmacología , Benzofuranos/farmacología , Ciclopropanos/farmacología , Indenos/farmacología , Receptores de Melatonina/agonistas , Receptores de Melatonina/antagonistas & inhibidores , Acetamidas/química , Animales , Benzofuranos/química , Ciclopropanos/química , Humanos , Indenos/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The binding constants (K(i) values) of 24 caracurine V and 6 iso-caracurine V analogues for the muscle type of nicotinic ACh receptors (nAChR) from Torpedo californica were determined in a binding assay using (+/-)-[(3)H]epibatidine as a radioligand. The allyl alcohol group present in the iso-caracurine V ring system was found to be essential for high binding affinity. The most potent compounds are the dimethyl and di-(4-nitrobenzyl)-iso-caracurinium V salts 29 (18 nM), and 31 (79 nM), respectively. Compound 29 and the corresponding diallyl analogue 30 (350 nM) exhibited similar binding affinities as the equally substituted neuromuscular-blocking agents toxiferine I (14 nM) and alcuronium (234 nM), respectively. The SAR results were confirmed by QSAR studies, which additionally revealed that the presence of hydrogen-bond acceptor groups close to the quaternary nitrogen, is detrimental for the nicotinic binding affinity. The diallyl- and dimethylcaracurinium V salts 13 and 27, respectively, which are known to be among the most potent allosteric modulators of M(2) receptors (EC(50)=10 and 8nM, respectively), exhibited rather low nicotinic binding affinities for muscle type nAChR (K(i)=1.5 and 5.2 microM, respectively). Such a large difference in affinity suggests that it is possible to develop compounds with high muscarinic allosteric potency and low or negligible affinities for (alpha1)(2)beta1gammadelta nAChR. Additionally, the iso-caracurine V analogues with binding affinities comparable to those of (+)-tubocurarine and alcuronium could become a new class of neuromuscular-blocking agents.
Asunto(s)
Alcaloides/química , Relación Estructura-Actividad Cuantitativa , Receptores Nicotínicos/química , Sitio Alostérico , Animales , Enlace de Hidrógeno , Isomerismo , Ligandos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Músculos , Bloqueantes Neuromusculares/química , Ensayo de Unión Radioligante , Receptor Muscarínico M2/química , Relación Estructura-Actividad , TorpedoRESUMEN
Bisquaternary dimers of strychnine and brucine were synthesized and their allosteric effect on muscarinic acetylcholine M(2) receptors was examined. The compounds retarded the dissociation of the antagonist [(3)H]N-methylscopolamine ([(3)H]NMS) from porcine cardiac cholinoceptors. This action indicated ternary complex formation. All compounds exhibited higher affinity to the allosteric site of [(3)H]NMS-occupied M(2) receptors than the monomeric strychnine and brucine, while the positive cooperativity with NMS was fully maintained. SAR studies revealed the unchanged strychnine ring as an important structural feature for high allosteric potency.
Asunto(s)
Receptor Muscarínico M2/metabolismo , Estricnina/análogos & derivados , Estricnina/química , Estricnina/metabolismo , Regulación Alostérica , Animales , Dimerización , Conformación Molecular , Antagonistas Muscarínicos/farmacología , N-Metilescopolamina/farmacología , Ensayo de Unión Radioligante , Receptor Muscarínico M2/efectos de los fármacos , Relación Estructura-Actividad , Estricnina/síntesis química , PorcinosRESUMEN
The allosteric effect on muscarinic acetylcholine M2 receptors of 11 bisquaternary salts of the Strychnos alkaloid caracurine V was determined. The effect was indicated by the concentration which retarded the rate of dissociation of the antagonist [3H]-N-methylscopolamine from porcine cardiac cholinoceptors by a factor of 2 (EC50). The most potent compounds carry allyl and propargyl substituents, respectively. Introduction of more bulky substituents (e.g., benzyl groups) resulted in a considerably reduced allosteric potency. The wide range of EC50 values (3 nM for R = allyl. 1750 nM for R = 2-naphthyl) suggests a sterically restricted binding pocket. Molecular modeling studies indicated that the caracurine V ring system satisfies the pharmacophore model for the allosteric interaction.
Asunto(s)
Alcaloides/farmacología , Receptores Muscarínicos/efectos de los fármacos , Alcaloides/química , Regulación Alostérica , Animales , Ligandos , Unión Proteica , Receptor Muscarínico M2 , Receptores Muscarínicos/metabolismo , PorcinosRESUMEN
The 3D structure of the Strychnos alkaloid caracurine V was determined by means of NMR spectroscopy and semiempirical calculations. The previously unknown absolute configuration in the central eight-membered ring was assigned as (16R, 16'R, 17R, and 17'R).