RESUMEN
N-Methyl-d-aspartate receptor (NMDAR) positive allosteric modulators (PAMs) have received increased interest as a powerful mechanism of action to provide relief as therapies for CNS disorders. Sage Therapeutics has previously published the discovery of endogenous neuroactive steroid 24(S)-hydroxycholesterol as an NMDAR PAM. In this article, we detail the discovery of development candidate SAGE-718 (5), a potent and high intrinsic activity NMDAR PAM with an optimized pharmacokinetic profile for oral dosing. Compound 5 has completed phase 1 single ascending dose and multiple ascending dose clinical trials and is currently undergoing phase 2 clinical trials for treatment of cognitive impairment in Huntington's disease.
Asunto(s)
Enfermedades del Sistema Nervioso Central , Disfunción Cognitiva , Neuroesteroides , Regulación Alostérica , Disfunción Cognitiva/tratamiento farmacológico , Humanos , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Neuroactive steroids (NASs) play a pivotal role in maintaining homeostasis is the CNS. We have discovered that one NAS in particular, 24(S)-hydroxycholesterol (24(S)-HC), is a positive allosteric modulator (PAM) of NMDA receptors. Using 24(S)-HC as a chemical starting point, we have identified other NASs that have good in vitro potency and efficacy. Herein, we describe the structure activity relationship and pharmacokinetic optimization of this series that ultimately led to SGE-301 (42). We demonstrate that SGE-301 enhances long-term potentiation (LTP) in rat hippocampal slices and, in a dose-dependent manner, improves cognition in a rat social recognition study.
Asunto(s)
Regulación Alostérica , Neuroesteroides/farmacología , Receptores de N-Metil-D-Aspartato/metabolismo , Factores de Edad , Animales , Cognición/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Humanos , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Metilación , Estructura Molecular , Neuroesteroides/química , Neuroesteroides/farmacocinética , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Endogenous and synthetic neuroactive steroids (NASs) or neurosteroids are effective modulators of multiple signaling pathways including receptors for the γ-aminobutyric acid A (GABAA) and glutamate, in particular N-methyl-d-aspartate (NMDA). These receptors are the major inhibitory and excitatory neurotransmitters in the central nervous system (CNS), and there is growing evidence suggesting that dysregulation of neurosteroid production plays a role in numerous neurological disorders. The significant unmet medical need for treatment of CNS disorders has increased the interest for these types of compounds. In this review, we highlight recent progress in the clinical development of NAS drug candidates, in addition to preclinical breakthroughs in the identification of novel NASs, mainly for GABAA and NMDA receptor modulation.
Asunto(s)
Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Descubrimiento de Drogas , Neurotransmisores/farmacología , Receptores de GABA-A/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Enfermedades del Sistema Nervioso Central/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Conformación Molecular , Neurotransmisores/química , Relación Estructura-ActividadRESUMEN
Certain classes of neuroactive steroids (NASs) are positive allosteric modulators (PAM) of synaptic and extrasynaptic GABAA receptors. Herein, we report new SAR insights in a series of 5ß-nor-19-pregnan-20-one analogues bearing substituted pyrazoles and triazoles at C-21, culminating in the discovery of 3α-hydroxy-3ß-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5ß-pregnan-20-one (SAGE-217, 3), a potent GABAA receptor modulator at both synaptic and extrasynaptic receptor subtypes, with excellent oral DMPK properties. Compound 3 has completed a phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) clinical trial and is currently being studied in parallel phase 2 clinical trials for the treatment of postpartum depression (PPD), major depressive disorder (MDD), and essential tremor (ET).
Asunto(s)
Regulación Alostérica/efectos de los fármacos , Agonistas de Receptores de GABA-A/química , Agonistas de Receptores de GABA-A/farmacología , Pregnanolona/análogos & derivados , Receptores de GABA-A/metabolismo , Animales , Depresión Posparto/tratamiento farmacológico , Trastorno Depresivo Mayor/tratamiento farmacológico , Femenino , Agonistas de Receptores de GABA-A/farmacocinética , Ratones , Pregnanolona/química , Pregnanolona/farmacocinética , Pregnanolona/farmacología , Pirazoles/química , Pirazoles/farmacocinética , Pirazoles/farmacología , RatasRESUMEN
Neuroactive steroids (NASs) have been shown to impact central nervous system (CNS) function through positive allosteric modulation of the GABA(A) receptor (GABA(A)-R). Herein we report the effects on the activity and pharmacokinetic properties of a series of nor-19 pregnanolone analogues bearing a heterocyclic substituent at C-21. These efforts resulted in the identification of SGE-516, a balanced synaptic/extrasynaptic GABA(A) receptor modulator, and SGE-872, a selective extrasynaptic GABA(A) receptor modulator. Both molecules possess excellent druglike properties, making them advanced leads for oral delivery of GABA(A) receptor modulators.
Asunto(s)
Neurotransmisores/química , Neurotransmisores/farmacología , Pregnanolona/análogos & derivados , Pregnanolona/farmacología , Receptores de GABA/metabolismo , Regulación Alostérica/efectos de los fármacos , Animales , Humanos , Ratones , Neurotransmisores/farmacocinética , Pregnanolona/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t(1/2), bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC(50)=1.4 nM), demonstrated high selectivity (>200×) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED=0.1mg/kg) and conditioned avoidance responding (CAR; ID(50)=0.2 mg/kg).
Asunto(s)
Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Triazinas/farmacología , Administración Oral , Animales , Cristalografía por Rayos X , Maleato de Dizocilpina/antagonistas & inhibidores , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Hipercinesia/inducido químicamente , Hipercinesia/tratamiento farmacológico , Modelos Moleculares , Estructura Molecular , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/química , Ratas , Relación Estructura-Actividad , Triazinas/administración & dosificación , Triazinas/químicaRESUMEN
The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound 1 and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC(50) for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.
Asunto(s)
Antipsicóticos/síntesis química , Inhibidores de Fosfodiesterasa/síntesis química , Hidrolasas Diéster Fosfóricas/metabolismo , Pirazinas/síntesis química , Administración Oral , Animales , Antipsicóticos/farmacocinética , Antipsicóticos/farmacología , Reacción de Prevención/efectos de los fármacos , Sitios de Unión , Cristalografía por Rayos X , AMP Cíclico/química , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Perros , Femenino , Humanos , Hidrólisis , Hipercinesia/tratamiento farmacológico , Técnicas In Vitro , Isoenzimas/química , Isoenzimas/metabolismo , Ligandos , Masculino , Ratones , Microsomas/metabolismo , Modelos Moleculares , Inhibidores de Fosfodiesterasa/farmacocinética , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/química , Conformación Proteica , Pirazinas/farmacocinética , Pirazinas/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Proteínas Recombinantes/química , Estereoisomerismo , Conducta Estereotipada/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
As part of an effort to identify 5-HT(1A) antagonists that did not possess typical arylalkylamine or keto/amido-alkyl aryl piperazine scaffolds, prototype compound 10a was identified from earlier work in a combined 5-HT(1A) antagonist/SSRI program. This quinolyl-piperazinyl piperidine analogue displayed potent, selective 5-HT(1A) antagonism but suffered from poor oxidative metabolic stability, resulting in low exposure following oral administration. SAR studies, driven primarily by in vitro liver microsomal stability assessment, identified compound 10b, which displayed improved oral bioavailability and lower intrinsic clearance. Further changes to the scaffold (e.g., 10r) resulted in a loss in potency. Compound 10b displayed cognitive enhancing effects in a number of animal models of learning and memory, enhanced the antidepressant-like effects of the SSRI fluoxetine, and reversed the sexual dysfunction induced by chronic fluoxetine treatment.
Asunto(s)
Piperazinas/síntesis química , Piperidinas/síntesis química , Quinolinas/síntesis química , Antagonistas del Receptor de Serotonina 5-HT1 , Acetilcolina/metabolismo , Administración Oral , Precursor de Proteína beta-Amiloide/genética , Animales , Antidepresivos/síntesis química , Antidepresivos/química , Antidepresivos/farmacología , Disponibilidad Biológica , Células CHO , Corteza Cerebral/metabolismo , Cognición/efectos de los fármacos , Cricetinae , Cricetulus , Fluoxetina/farmacología , Hipocampo/metabolismo , Técnicas In Vitro , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Ratones , Ratones Transgénicos , Microsomas Hepáticos/metabolismo , Nootrópicos/síntesis química , Nootrópicos/química , Nootrópicos/farmacología , Erección Peniana/efectos de los fármacos , Piperazinas/química , Piperazinas/farmacología , Piperidinas/química , Piperidinas/farmacología , Quinolinas/química , Quinolinas/farmacología , Ratas , Serotonina/metabolismo , Relación Estructura-ActividadRESUMEN
Novel imidazo[1,5-a]pyrido[3,2-e]pyrazines have been synthesized and characterized as both potent and selective phosphodiesterase 10A (PDE10A) inhibitors. For in vitro characterization, inhibition of PDE10A mediated cAMP hydrolysis was used and a QSAR model was established to analyze substitution effects. The outcome of this analysis was complemented by the crystal structure of PDE10A in complex with compound 49. Qualitatively new interactions between inhibitor and binding site were found, contrasting with previously published crystal structures of papaverine-like inhibitors. In accordance with the known antipsychotic potential of PDE10A inhibitors, MK-801 induced stereotypy and hyperactivity in rats were reversed by selected compounds. Thus, a promising compound class has been identified for the treatment of schizophrenia that could circumvent side effects connected with current therapies.
Asunto(s)
Descubrimiento de Drogas/métodos , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Pirazinas/química , Pirazinas/farmacología , Animales , Femenino , Humanos , Modelos Moleculares , Hidrolasas Diéster Fosfóricas/química , Conformación Proteica , Relación Estructura-Actividad Cuantitativa , Ratas , Ratas WistarRESUMEN
Novel 3-(arylsulfonyl)-1-(azacyclyl)-1H-indoles 6 were synthesized as potential 5-HT(6) receptor ligands, based on constraining a basic side chain as either a piperidine or a pyrrolidine. Many of these compounds had good 5-HT(6) binding affinity with K(i) values <10nM. Depending on substitution, both agonists (e.g., 6o: EC(50)=60nM, E(max)=70%) and antagonists (6y: IC(50)=17 nM, I(max)=86%) were identified in a 5-HT(6) adenylyl cyclase assay.
Asunto(s)
Indoles/química , Receptores de Serotonina/química , Antagonistas de la Serotonina/química , Agonistas de Receptores de Serotonina/química , Sulfonas/química , Humanos , Indoles/síntesis química , Indoles/farmacología , Ligandos , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/síntesis química , Agonistas de Receptores de Serotonina/farmacología , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/farmacologíaRESUMEN
Several benzofuran derivatives linked to a 3-indoletetrahydropyridine through an alkyl chain were prepared and evaluated for serotonin transporter and 5-HT(1A) receptor affinities. Their design, synthesis and structure-activity relationships are described.
Asunto(s)
Benzofuranos/química , Benzofuranos/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Unión Proteica/fisiología , Relación Estructura-ActividadRESUMEN
The structure-activity relationship (SAR) for three series of lactam-fused chroman derivatives possessing 3-amino substituents was evaluated. Many compounds exhibited affinities for both the 5-HT(1A) receptor and the 5-HT transporter. Compounds 45 and 53 demonstrated 5-HT(1A) antagonist activities in the in vitro cAMP turnover model.
Asunto(s)
Cromanos/química , Lactamas/química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Antagonistas del Receptor de Serotonina 5-HT1 , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Cromanos/síntesis química , Cromanos/farmacología , AMP Cíclico/metabolismo , Diseño de Fármacos , Receptor de Serotonina 5-HT1A/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-pyrrolopyridines were prepared. Binding assays indicated they are 5-HT(6) receptor ligands, among which 6f and 6g showed high affinity for 5-HT(6) receptors with K(i)=3.9 and 1.7 nM, respectively.
Asunto(s)
Piridinas/farmacología , Pirroles/farmacología , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Células HeLa , Humanos , Ligandos , Piridinas/química , Pirroles/química , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/química , Agonistas de Receptores de Serotonina/químicaRESUMEN
Cysteine-dependant aspartyl protease (caspase) activation has been implicated as a part of the signal transduction pathway leading to apoptosis. It has been postulated that caspase-3 inhibition could attenuate cell damage after an ischemic event and thereby providing for a novel neuroprotective treatment for stroke. As part of a program to develop a small molecule inhibitor of caspase-3, a novel series of 3,4-dihydropyrimido(1,2-a)indol-10(2H)-ones (pyrimidoindolones) was identified. The synthesis, biological evaluation and structure-activity relationships of the pyrimidoindolones are described.
Asunto(s)
Inhibidores de Caspasas , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Pirimidinonas/química , Pirimidinonas/farmacología , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Línea Celular , Escherichia coli , Inhibidores de Proteasas/síntesis química , Pirimidinonas/síntesis química , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Relación Estructura-ActividadRESUMEN
On the basis of the previously reported clinical candidate, SSA-426 (1), a series of related 2-piperazin-1-ylquinoline derivatives 3-16 were synthesized and evaluated as dual-acting serotonin (5-HT) reuptake inhibitors and 5-HT1A receptor antagonists. In particular, compound 7 exhibits potent functional activities at both the 5-HT transporter and 5-HT1A receptor, good selectivity over the alpha1-adrenergic and dopaminergic receptors, acceptable pharmacokinetic properties, and a favorable in vivo profile.
Asunto(s)
Piperazinas/síntesis química , Quinolinas/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Antagonistas del Receptor de Serotonina 5-HT1 , Antagonistas de la Serotonina/síntesis química , Animales , Antidepresivos/farmacología , Células CHO , Cricetinae , Cricetulus , Inhibidores Enzimáticos del Citocromo P-450 , Humanos , Microdiálisis , Piperazinas/farmacología , Quinolinas/farmacología , Ratas , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Dopaminérgicos/metabolismo , Antagonistas de la Serotonina/farmacocinética , Antagonistas de la Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
A series of 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 10a-z was prepared as novel 5-HT(6) ligands. The best compounds were high affinity, full agonists at 5-HT(6) receptors. Several agonists demonstrated good selectivity over other serotonergic and dopaminergic receptors. Acute administration of selective agonist 10e significantly increased extracellular GABA concentrations in rat frontal cortex. This compound also reduced adjunctive drinking behavior in the rat schedule-induced polydipsia assay, possibly predictive of efficacy in obsessive compulsive disorder and other anxiety related disorders.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Conducta de Ingestión de Líquido/efectos de los fármacos , Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/farmacología , Animales , Corteza Cerebral/metabolismo , Ácido Glutámico/análisis , Ácido Glutámico/metabolismo , Células HeLa , Humanos , Unión Proteica , Ratas , Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/síntesis química , Ácido gamma-Aminobutírico/análisis , Ácido gamma-Aminobutírico/metabolismoRESUMEN
gamma-Secretase inhibitors have been shown to reduce the production of beta-amyloid, a component of the plaques that are found in brains of patients with Alzheimer's disease. A novel series of heterocyclic sulfonamide gamma-secretase inhibitors that reduce beta-amyloid levels in cells is reported. Several examples of compounds within this series demonstrate a higher propensity to inhibit the processing of amyloid precursor protein compared to Notch, an alternative gamma-secretase substrate.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Células CHO , Cricetinae , Cricetulus , Compuestos Heterocíclicos/síntesis química , Humanos , Estructura Molecular , Unión Proteica , Receptores Notch/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis químicaRESUMEN
Accumulation of beta-amyloid (Abeta), produced by the proteolytic cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase, is widely believed to be associated with Alzheimer's disease (AD). Research around the high-throughput screening hit (S)-4-chlorophenylsulfonyl isoleucinol led to the identification of the Notch-1-sparing (9.5-fold) gamma-secretase inhibitor (S)-N-(5-chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol 7.b.2 (Abeta(40/42) EC(50)=28 nM), which is efficacious in reduction of Abeta production in vivo.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Isoleucina/análogos & derivados , Receptor Notch1/metabolismo , Alcoholes , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/química , Animales , Diseño de Fármacos , Humanos , Isoleucina/química , Modelos Químicos , Propanolaminas/química , Sulfonamidas/químicaRESUMEN
Novel compounds combining a 5-HT 1A moiety (3-aminochroman scaffold) and a 5-HT transporter (indole analogues) linked through a common basic nitrogen via an alkyl chain attached at the 1- or 3-position of the indole were evaluated for dual affinity at both the 5-HT reuptake site and the 5-HT 1A receptor. Compounds of most interest were found to have a 5-carbamoyl-8-fluoro-3-amino-3,4-dihydro-2 H-1-benzopyran linked to a 3-alkylindole (straight chain), more specifically substituted with a 5-fluoro (( R)-(-)- 35c), 5-cyano ((-)- 52a), or 5,7-difluoro ((-)- 52g). Several factors contributed to 5-HT 1A affinity, serotonin rat transporter affinity, and functional antagonism in vitro. Although most of our analogues showed good to excellent affinities at both targets, specific features such as cyclobutyl substitution on the basic nitrogen and stereochemistry at the 3-position of the chroman moiety seemed necessary for antagonism at the 5-HT 1A receptor. Branched linkers seemed to impart antagonism even as racemates; however, the potency of these analogues in the functional assay was not desirable enough to further pursue these compounds.
Asunto(s)
Antidepresivos/síntesis química , Antidepresivos/farmacología , Benzopiranos/síntesis química , Benzopiranos/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Antagonistas del Receptor de Serotonina 5-HT1 , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Animales , Antidepresivos/química , Benzopiranos/química , Línea Celular , Cricetinae , Reactivos de Enlaces Cruzados/química , Humanos , Estructura Molecular , Ratas , Receptor de Serotonina 5-HT1A/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
Based on the previously reported discovery lead, 3-(cis-4-(4-(1H-indol-4-yl)piperazin-1-yl)cyclohexyl)-5-fluoro-1H-indole (2), a series of related arylpiperazin-4-yl-cyclohexyl indole analogs were synthesized then evaluated as 5-HT transporter inhibitors and 5-HT(1A) receptor antagonists. The investigation of the structure-activity relationships revealed the optimal pharmacophoric elements required for activities in this series. The best example from this study, 5-(piperazin-1-yl)quinoline analog (trans-20), exhibited equal binding affinities at 5-HT transporter (K(i)=4.9nM), 5-HT(1A) receptor (K(i)=6.2nM) and functioned as a 5-HT(1A) receptor antagonist.