RESUMEN
The identification of new sleep drugs poses particular challenges in drug discovery owing to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging when interspecies differences are prominent. This report describes the discovery of the dual orexin receptor 1 and 2 (OX1 and OX2) antagonist ACT-541468 out of a class of structurally related compounds, by use of physiology-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling applied early in drug discovery. Although all drug candidates exhibited similar target receptor potencies and efficacy in a rat sleep model, they exhibited large interspecies differences in key factors determining their pharmacokinetic profile. Human PK models were built on the basis of in vitro metabolism and physicochemical data and were then used to predict the time course of OX2 receptor occupancy in brain. An active ACT-541468 dose of 25 mg was estimated on the basis of OX2 receptor occupancy thresholds of about 65% derived from clinical data for two other orexin antagonists, almorexant and suvorexant. Modeling predictions for ACT-541468 in man were largely confirmed in a single-ascending dose trial in healthy subjects. PBPK-PD modeling applied early in drug discovery, therefore, has great potential to assist in the identification of drug molecules when specific pharmacokinetic and pharmacodynamic requirements need to be met.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Descubrimiento de Drogas/métodos , Imidazoles/farmacocinética , Antagonistas de los Receptores de Orexina/farmacocinética , Pirrolidinas/farmacocinética , Animales , Células CHO , Cricetinae , Cricetulus , Perros , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Masculino , Ratas , Ratas WistarRESUMEN
Starting from advanced pyrrolidin-2-one lead compounds, this novel series of small-molecule orexin receptor antagonists was further optimized by fine-tuning of the C-3 substitution at the γ-lactam ring. We discuss our design to align in vitro potency with metabolic stability and improved physicochemical/pharmacokinetic properties while avoiding P-glycoprotein-mediated efflux. These investigations led to the identification of the orally active 3-hydroxypyrrolidin-2-one 46, a potent and selective orexin-2 receptor antagonist, that achieved good brain exposure and promoted physiological sleep in rats.
Asunto(s)
Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/metabolismo , Pirrolidinonas/farmacología , Sueño/efectos de los fármacos , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Humanos , Lactamas/administración & dosificación , Lactamas/farmacología , Estructura Molecular , Antagonistas de los Receptores de Orexina/síntesis química , Antagonistas de los Receptores de Orexina/química , Pirrolidinonas/síntesis química , Pirrolidinonas/química , Ratas , Relación Estructura-ActividadRESUMEN
Starting from a thiazolidin-4-one HTS hit, a novel series of substituted lactams was identified and developed as dual orexin receptor antagonists. In this Letter, we describe our initial efforts towards the improvement of potency and metabolic stability. These investigations delivered optimized lead compounds with CNS drug-like properties suitable for further optimization.
Asunto(s)
Descubrimiento de Drogas , Lactamas/farmacología , Antagonistas de los Receptores de Orexina , Animales , Relación Dosis-Respuesta a Droga , Humanos , Lactamas/química , Lactamas/metabolismo , Estructura Molecular , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Orexins are hypothalamic peptides that play an important role in maintaining wakefulness in mammals. Permanent deficit in orexinergic function is a pathophysiological hallmark of rodent, canine and human narcolepsy. Here we report that in rats, dogs and humans, somnolence is induced by pharmacological blockade of both orexin OX(1) and OX(2) receptors. When administered orally during the active period of the circadian cycle, a dual antagonist increased, in rats, electrophysiological indices of both non-REM and, particularly, REM sleep, in contrast to GABA(A) receptor modulators; in dogs, it caused somnolence and increased surrogate markers of REM sleep; and in humans, it caused subjective and objective electrophysiological signs of sleep. No signs of cataplexy were observed, in contrast to the rodent, dog or human narcolepsy syndromes. These results open new perspectives for investigating the role of endogenous orexins in sleep-wake regulation.
Asunto(s)
Acetamidas/farmacología , Hipotálamo Posterior/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Isoquinolinas/farmacología , Neuropéptidos/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Sueño REM/efectos de los fármacos , Tetrahidroisoquinolinas/farmacología , Acetamidas/farmacocinética , Animales , Perros , Electroencefalografía , Femenino , Humanos , Hipotálamo Posterior/metabolismo , Péptidos y Proteínas de Señalización Intracelular/fisiología , Isoquinolinas/farmacocinética , Masculino , Neuropéptidos/fisiología , Receptores de Orexina , Orexinas , Ratas , Factores Sexuales , Transducción de Señal/fisiología , Tetrahidroisoquinolinas/farmacocinéticaRESUMEN
Dual orexin receptor (OXR) antagonists emerge as a novel therapeutic class to treat insomnia that, based on anti-addictive effects of selective OXR type 1 antagonists in rats, might be associated with less abuse liability than commonly used γ-aminobutyric acid (GABA) receptor modulators. Here, we studied the effects of the sleep-enabling dual OXR antagonist almorexant on conditioned place preference (CPP) and locomotor sensitization in rats. First, we compared almorexant to the GABA metabolite γ-hydroxybutyrate (GHB), which is clinically used as a sleep-inducing drug and which is associated with mild abuse liability. Whereas conditioning with GHB induced significant place preference, conditioning with almorexant did not. Second, we tested the potential of almorexant to interfere with the conditioned rewarding or locomotor sensitizing effects related to psychostimulants or opiates. Almorexant attenuated the expression of CPP to high doses of cocaine (15 mg/kg) and d.l-amphetamine (2 mg/kg), but not to high dose of morphine (10 mg/kg). Conversely, almorexant interfered with the expression of locomotor sensitization to morphine, but not with that to cocaine and d.l-amphetamine. Third, we observed that chronic almorexant (12 d) treatment in morphine, cocaine or amphetamine pre-conditioned and locomotor-sensitized rats had no influence on the maintenance of CPP and locomotor sensitization when tested after almorexant washout. Our findings suggest that almorexant itself does not exert conditioned rewarding effects in the rat and that it may acutely interfere with the expression of CPP or locomotor sensitization in a drug-dependent manner (monoaminergic psychostimulants vs. opiates).
Asunto(s)
Acetamidas/farmacología , Anestésicos/farmacología , Condicionamiento Operante/efectos de los fármacos , Dopaminérgicos/farmacología , Flavoproteínas/agonistas , Isoquinolinas/farmacología , Locomoción/efectos de los fármacos , Anfetamina/farmacología , Animales , Cocaína/farmacología , Interacciones Farmacológicas , Oxidasas Duales , Masculino , Morfina/farmacología , Ratas , Ratas Sprague-Dawley , RecompensaRESUMEN
A novel series of non-peptidic OX1R/OX2R orexin receptor antagonists was prepared by heterocyclic replacement of the dimethoxyphenyl moiety contained in the tetrahydroisoquinoline core skeleton of almorexant. Introduction of substituted imidazole moieties delivered potent dual orexin receptor antagonists with nanomolar potency for hOX1R and hOX2R suitable for further fine-tuning. The preparation of these novel orexin receptor antagonists and the outcome of preliminary structure-activity relationship studies are described in this communication.
Asunto(s)
Pirazinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Receptores de Orexina , Pirazinas/síntesis química , Pirazinas/química , Relación Estructura-ActividadRESUMEN
Replacement of the dimethoxyphenyl moiety in the core skeleton of almorexant by appropriately substituted imidazoles afforded novel 1-chloro-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine derivatives as potent dual orexin receptor antagonists. We describe in this Letter our efforts to further optimize the potency and brain penetration of these derivatives by fine-tuning of the pivotal phenethyl motif, and we comment on the sleep-promoting activity of selected compounds in a rat electroencephalographic (EEG) model.
Asunto(s)
Imidazoles/farmacología , Antagonistas de los Receptores de Orexina , Pirazinas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Imidazoles/síntesis química , Imidazoles/química , Estructura Molecular , Pirazinas/síntesis química , Pirazinas/química , Relación Estructura-ActividadRESUMEN
A novel series of dual orexin receptor antagonists was prepared by heteroaromatic five-membered ring system replacement of the dimethoxyphenyl moiety contained in the tetrahydroisoquinoline core skeleton of almorexant. Thus, replacement of the dimethoxyphenyl by a substituted pyrazole and additional optimization of the substitution pattern of the phenethyl motif allowed the identification of potent antagonists with low nanomolar affinity for hOX(1)R and hOX(2)R. The synthesis and structure-activity relationship of these novel antagonists will be discussed in this communication. These investigations furnished several suitable candidates for further evaluation in in vivo studies in rats.
Asunto(s)
Pirazoles/química , Piridinas/química , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Acetamidas/química , Acetamidas/farmacología , Animales , Isoquinolinas/química , Isoquinolinas/farmacología , Receptores de Orexina , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropéptido/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The orexin system is responsible for regulating the sleep-wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5-methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[5-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-1-yl}methanone (6), a compound which emerged from our in-house research program. Compound 6 was shown to be a potent, brain-penetrating DORA with inâ vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (fu brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above-mentioned shortcomings resulted in the identification of (4-chloro-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-methyl-2-[5-(2-trifluoromethoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-pyrrolidin-1-yl}l-methanone (42), a DORA with improved inâ vivo efficacy compared to 6.
Asunto(s)
Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/metabolismo , Oxadiazoles/farmacología , Triazoles/farmacología , Animales , Perros , Masculino , Conformación Molecular , Antagonistas de los Receptores de Orexina/química , Oxadiazoles/química , Ratas , Ratas Wistar , Sueño/efectos de los fármacos , Estereoisomerismo , Triazoles/químicaRESUMEN
The orexin system plays an important role in the regulation of wakefulness. Suvorexant, a dual orexin receptor antagonist (DORA) is approved for the treatment of primary insomnia. Herein, we outline our optimization efforts toward a novel DORA. We started our investigation with rac-[3-(5-chloro-benzooxazol-2-ylamino)piperidin-1-yl]-(5-methyl-2-[1,2,3]triazol-2-ylphenyl)methanone (3), a structural hybrid of suvorexant and a piperidine-containing DORA. During the optimization, we resolved liabilities such as chemical instability, CYP3A4 inhibition, and low brain penetration potential. Furthermore, structural modification of the piperidine scaffold was essential to improve potency at the orexinâ 2 receptor. This work led to the identification of (5-methoxy-4-methyl-2-[1,2,3]triazol-2-ylphenyl)-{(S)-2-[5-(2-trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]pyrrolidin-1-yl}methanone (51), a potent, brain-penetrating DORA with inâ vivo efficacy similar to that of suvorexant in rats.
Asunto(s)
Antagonistas de los Receptores de Orexina/síntesis química , Receptores de Orexina/metabolismo , Oxadiazoles/química , Animales , Azepinas/farmacología , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Perros , Semivida , Humanos , Concentración 50 Inhibidora , Antagonistas de los Receptores de Orexina/metabolismo , Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/química , Oxadiazoles/metabolismo , Oxadiazoles/farmacología , Ratas , Sueño/efectos de los fármacos , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
A series of dual OX(1)R/OX(2)R orexin antagonists was prepared based on a N-glycine-sulfonamide core. SAR studies of a screening hit led to compounds with low nanomolar affinity for both receptors and good oral bioavailability. One of these compounds, 47, has demonstrated in vivo activity in rats following oral administration.
Asunto(s)
Glicina/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Sulfonamidas/farmacología , Animales , Disponibilidad Biológica , Barrera Hematoencefálica , Glicina/química , Glicina/farmacocinética , Masculino , Receptores de Orexina , Ratas , Ratas Wistar , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMEN
Starting from suvorexant (trade name Belsomra), we successfully identified interesting templates leading to potent dual orexin receptor antagonists (DORAs) via a scaffold-hopping approach. Structure-activity relationship optimization allowed us not only to improve the antagonistic potency on both orexinâ 1 and orexinâ 2 receptors (Ox1 and Ox2, respectively), but also to increase metabolic stability in human liver microsomes (HLM), decrease time-dependent inhibition of cytochrome P450 (CYP) 3A4, and decrease P-glycoprotein (Pgp)-mediated efflux. Compound 80 c [{(1S,6R)-3-(6,7-difluoroquinoxalin-2-yl)-3,8-diazabicyclo[4.2.0]octan-8-yl}(4-methyl-[1,1'-biphenyl]-2-yl)methanone] is a potent and selective DORA that inhibits the stimulating effects of orexin peptides OXA and OXB at both Ox1 and Ox2. In calcium-release assays, 80 c was found to exhibit an insurmountable antagonistic profile at both Ox1 and Ox2, while displaying a sleep-promoting effect in rat and dog models, similar to that of the benchmark compound suvorexant.
Asunto(s)
Inhibidores del Citocromo P-450 CYP3A/farmacología , Descubrimiento de Drogas , Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/metabolismo , Animales , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/síntesis química , Inhibidores del Citocromo P-450 CYP3A/química , Perros , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Antagonistas de los Receptores de Orexina/síntesis química , Antagonistas de los Receptores de Orexina/química , Ratas , Ratas Wistar , Sueño/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
RATIONALE: Avoidance of contexts directly associated with fearful experiences represents an adaptive behavioral survival strategy. Over-interpretation of contextual cues leading to generalized avoidance of situations that are only remotely similar to the original fear context represents a pathologic process that contributes to anxiety disorders. Orexin neuropeptides modulate anxiety-like behavioral and physiological responses. OBJECTIVE: The objective of this paper was to investigate the impact of pharmacological orexin receptor blockade on generalized avoidance behavior. METHODS: Rats received a single electric foot-shock in the dark side of a two-compartment shuttle box followed by situational context reminders. After shock, rats were treated chronically (3 weeks) with the orexin receptor antagonist almorexant or with the selective serotonin reuptake inhibitor sertraline, used as positive anxiolytic control. In week 3, avoidance behavior was measured under conditions of high (dark-light (DL)-box) and low (elevated plus maze (EPM)) similarity to the original shock context. Avoidance behavior was re-assessed 5 and 17 weeks after treatment termination. RESULTS: Avoidance in the DL box (contextual fear memory) remained unaffected by any treatment and lasted 20 weeks post-shock exposure. Avoidance in the EPM (neophobic fear generalization) was partially attenuated during treatment with almorexant and sertraline at week 3. Following 5 and 17 weeks of drug washout, avoidance in the EPM was significantly reduced in almorexant- but not in sertraline-treated rats. Almorexant also reduced persistent avoidance in the EPM upon treatment initiation 3 weeks after shock exposure. CONCLUSION: Chronic orexin receptor blockade in rats reduces both the development and persistence of generalized avoidance in situations with low similarity to the initial shock context.
Asunto(s)
Reacción de Prevención/fisiología , Electrochoque/psicología , Miedo/fisiología , Miedo/psicología , Antagonistas de los Receptores de Orexina , Receptores de Orexina/fisiología , Acetamidas/farmacología , Acetamidas/uso terapéutico , Animales , Reacción de Prevención/efectos de los fármacos , Electrochoque/efectos adversos , Miedo/efectos de los fármacos , Isoquinolinas/farmacología , Isoquinolinas/uso terapéutico , Masculino , Memoria/efectos de los fármacos , Memoria/fisiología , Ratas , Ratas Sprague-Dawley , Sertralina/farmacología , Sertralina/uso terapéuticoRESUMEN
Novel hexahydrospiro[piperidine-4,1'-pyrrolo[3,4-c]pyrroles that act as potent and selective orphanin FQ/nociceptin (N/OFQ) receptor (NOP) agonists were identified. The best compound, (+)-5a, potently inhibited 3H-N/OFQ binding to the NOP receptor (K(i) = 0.49 nM) but was >1000-fold less potent in binding to MOP, KOP, and DOP opiate receptors. Further, (+)-5a potently stimulated GTP gamma S binding to NOP membranes (EC50 = 65 nM) and inhibited forskolin-mediated cAMP accumulation in NOP-expressing cells (EC50 = 9.1 nM) with a potency comparable to that of the natural peptide agonist N/OFQ. These results indicate that (+)-5a is a highly selective and potent small-molecule full agonist of the NOP receptor.
Asunto(s)
Piridinas/síntesis química , Pirroles/síntesis química , Receptores Opioides/agonistas , Compuestos de Espiro/síntesis química , Unión Competitiva , Línea Celular , Cristalografía por Rayos X , AMP Cíclico/antagonistas & inhibidores , AMP Cíclico/biosíntesis , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Piridinas/química , Piridinas/farmacología , Pirroles/química , Pirroles/farmacología , Ensayo de Unión Radioligante , Receptores Opioides delta/agonistas , Receptores Opioides kappa/agonistas , Receptores Opioides mu/agonistas , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Receptor de NociceptinaRESUMEN
RATIONALE: (1S,3aS)-8-(2,3,3,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198), a non-peptidic agonist for the opioid receptor-like1 (ORL1) receptor, exhibits anxiolytic properties in stressful conditions. OBJECTIVE: The present study was aimed at evaluating whether activation of ORL1 receptors by Ro 64-6198 may reverse the anorectic effect of restraint stress or intracerebroventricular (ICV) CRF injection. METHODS: In body restraint experiments, 20-h food deprived rats were treated with intraperitoneal (IP) injection of Ro 64-6198 or vehicle. Ten minutes later, they were confined in cylindrical Plexiglas tubes for 60 min and then returned to their cage with food. In CRF experiments, 20-h food deprived rats were IP injected with Ro 64-6198 or vehicle. Ten minutes later, they received ICV CRF, 200 ng/rat or vehicle; food was offered after 20 min. RESULTS: Intraperitoneal (IP) pretreatment with Ro 64-6198 reversed the hypophagic effect induced by both restraint or CRF; the effect was statistically significant at the three doses tested (0.3, 1.0 or 2.5 mg/kg). ICV administration of the selective ORL1 receptor antagonist [Nphe(1)]NC(1-13)NH(2)(two injections of 33 or 66 microg/rat) abolished the effect of Ro 64-6198 on CRF-induced anorexia. In freely feeding rats, Ro 64-6198 significantly increased feeding at 2.5, but not at 0.3 or 1.0 mg/kg; in food deprived rats, Ro 64-6198 (0.3 or 1.0 mg/kg) did not modify food intake. Thus, reversal of stress- and CRF-induced anorexia by Ro 64-6198 can be evoked at doses lower than those that are hyperphagic. Ro 64-6198 (1 or 2.5 mg/kg) did not modify the anorectic effect of E. coli lipopolysaccharide, suggesting that its effect is selective for stress- or CRF-induced anorexia. Lastly, the benzodiazepine diazepam was unable to reduce the anorectic effect of CRF at the anxiolytic dose of 0.3 mg/kg, and partially reduced it at the hyperphagic dose of 1 mg/kg. CONCLUSIONS: The results of this study show that the non-peptidic ORL1 receptor agonist Ro 64-6198 markedly and selectively inhibits the anorectic effect of stress and CRF, and provide evidence that this effect is mediated by ORL1 receptors. Thus, Ro 64-6198 may represent an interesting tool for treatment of stress-induced anorexia.
Asunto(s)
Anorexia/inducido químicamente , Anorexia/tratamiento farmacológico , Ansiolíticos/uso terapéutico , Hormona Liberadora de Corticotropina/efectos adversos , Imidazoles/uso terapéutico , Péptidos Opioides/metabolismo , Receptores Opioides/agonistas , Compuestos de Espiro/uso terapéutico , Estrés Fisiológico/tratamiento farmacológico , Animales , Masculino , Ratas , Ratas Wistar , Receptor de Nociceptina , NociceptinaRESUMEN
The abuse liability of Ro 64-6198, an orphanin FQ (OFQ) receptor full agonist that exhibits anxiolytic properties, was evaluated using an unbiased conditioned place preference (CPP) paradigm in rats. As OFQ is structurally related to opioid peptides and also exhibits anxiolytic-like properties, the effect of Ro 64-6198 on CPP was compared with those of morphine and alprazolam. We show here that neither Ro 64-6198 nor alprazolam exhibited rewarding or aversive properties, whereas morphine induced a pronounced CPP. These results strengthen the previous finding that Ro 64-6198 lacked abuse liability in a self-stimulation paradigm, suggesting that this new class of anxiolytic drugs is devoid of the risk for potential non-medical use and dependence.
Asunto(s)
Ansiolíticos/farmacología , Condicionamiento Operante/efectos de los fármacos , Imidazoles/farmacología , Receptores Opioides/agonistas , Compuestos de Espiro/farmacología , Alprazolam/farmacología , Analgésicos Opioides/farmacología , Animales , Condicionamiento Operante/fisiología , Relación Dosis-Respuesta a Droga , Masculino , Morfina/farmacología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Ratas , Ratas Sprague-Dawley , Receptores Opioides/fisiología , Receptor de NociceptinaRESUMEN
The orexin system consists of two G-protein-coupled receptors, the orexin 1 and orexin 2 receptors, widely expressed in diverse regions of the brain, and two peptide agonists, orexin A and orexin B, which are produced in a small assembly of neurons in the lateral hypothalamus. The orexin system plays an important role in the maintenance of wakefulness. Several compounds (almorexant, SB-649868, suvorexant) have been in advanced clinical trials for treating primary insomnia. ACT-462206 is a new, potent, and selective dual orexin receptor antagonist (DORA) that inhibits the stimulating effects of the orexin peptides at both the orexin 1 and 2 receptors. It decreases wakefulness and increases non-rapid eye movement (non-REM) and REM sleep while maintaining natural sleep architectures in rat and dog electroencephalography/electromyography (EEG/EMG) experiments. ACT-462206 shows anxiolytic-like properties in rats without affecting cognition and motor function. It is therefore a potential candidate for the treatment of insomnia.
Asunto(s)
Encéfalo/metabolismo , Neurotransmisores/química , Antagonistas de los Receptores de Orexina , Pirrolidinas/química , Sulfonamidas/química , Animales , Barrera Hematoencefálica/metabolismo , Perros , Semivida , Humanos , Células de Riñón Canino Madin Darby , Masculino , Neurotransmisores/farmacocinética , Receptores de Orexina/metabolismo , Prolina/química , Pirrolidinas/farmacocinética , Ratas , Ratas Wistar , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinéticaRESUMEN
The orexin system regulates feeding, nutrient metabolism and energy homeostasis. Acute pharmacological blockade of orexin receptor 1 (OXR-1) in rodents induces satiety and reduces normal and palatable food intake. Genetic OXR-1 deletion in mice improves hyperglycemia under high-fat (HF) diet conditions. Here we investigated the effects of chronic treatment with the novel selective OXR-1 antagonist ACT-335827 in a rat model of diet-induced obesity (DIO) associated with metabolic syndrome (MetS). Rats were fed either standard chow (SC) or a cafeteria (CAF) diet comprised of intermittent human snacks and a constant free choice between a HF/sweet (HF/S) diet and SC for 13 weeks. Thereafter the SC group was treated with vehicle (for 4 weeks) and the CAF group was divided into a vehicle and an ACT-335827 treatment group. Energy and water intake, food preference, and indicators of MetS (abdominal obesity, glucose homeostasis, plasma lipids, and blood pressure) were monitored. Hippocampus-dependent memory, which can be impaired by DIO, was assessed. CAF diet fed rats treated with ACT-335827 consumed less of the HF/S diet and more of the SC, but did not change their snack or total kcal intake compared to vehicle-treated rats. ACT-335827 increased water intake and the high-density lipoprotein associated cholesterol proportion of total circulating cholesterol. ACT-335827 slightly increased body weight gain (4% vs. controls) and feed efficiency in the absence of hyperphagia. These effects were not associated with significant changes in the elevated fasting glucose and triglyceride (TG) plasma levels, glucose intolerance, elevated blood pressure, and adiposity due to CAF diet consumption. Neither CAF diet consumption alone nor ACT-335827 affected memory. In conclusion, the main metabolic characteristics associated with DIO and MetS in rats remained unaffected by chronic ACT-335827 treatment, suggesting that pharmacological OXR-1 blockade has minimal impact in this model.
RESUMEN
The orexin neuropeptide system regulates wakefulness and contributes to physiological and behavioral stress responses. Moreover, a role for orexins in modulating hypothalamus-pituitary-adrenal (HPA) axis activity has been proposed. Brain penetrating dual orexin receptor (OXR) antagonists such as almorexant decrease vigilance and have emerged as a novel therapeutic class for the treatment of insomnia. Almorexant was used here as a pharmacological tool to examine the role of endogenous orexin signaling in HPA axis endocrine function under natural conditions. After confirming the expression of prepro-orexin and OXR-1 and OXR-2 mRNA in hypothalamus, pituitary and adrenal glands, the effects of systemic almorexant were investigated on peripheral HPA axis hormone release in the rat under baseline, stress and pharmacological challenge conditions. Almorexant did not alter basal or stress-induced corticosterone release despite affecting wake and sleep stages (detected by radiotelemetric electroencephalography/electromyography) during the stress exposure. Moreover, almorexant did not affect the release of adrenocorticotropin (ACTH) and corticosterone at different time points along the diurnal rhythm, nor corticotrophin-releasing hormone (CRH)- and ACTH-stimulated neuroendocrine responses, measured in vivo under stress-free conditions. These results illustrate that dual OXR antagonists, despite modulating stress-induced wakefulness, do not interfere with endocrine HPA axis function in the rat. They converge to suggest that endogenous orexin signaling plays a minor role in stress hormone release under basal conditions and under challenge.
Asunto(s)
Acetamidas/farmacología , Glándulas Suprarrenales/metabolismo , Péptidos y Proteínas de Señalización Intracelular/fisiología , Isoquinolinas/farmacología , Neuropéptidos/fisiología , Antagonistas de los Receptores de Orexina , Hipófisis/metabolismo , Hormona Adrenocorticotrópica/sangre , Animales , Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/fisiología , Corticosterona/sangre , Hormona Liberadora de Corticotropina/farmacología , Hipnóticos y Sedantes/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/fisiología , Hipotálamo/metabolismo , Péptidos y Proteínas de Señalización Intracelular/biosíntesis , Masculino , Neuropéptidos/biosíntesis , Receptores de Orexina/biosíntesis , Orexinas , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/fisiología , Ratas , Restricción Física/fisiología , Fases del Sueño/efectos de los fármacos , Vigilia/efectos de los fármacosRESUMEN
Stress relief: Orexin neuropeptides regulate arousal and stress processing through orexin receptor type 1 (OXR-1) and 2 (OXR-2) signaling. A selective OXR-1 antagonist, represented by a phenylglycine-amide substituted tetrahydropapaverine derivative (ACT-335827), is described that is orally available, penetrates the brain, and decreases fear, compulsive behaviors and autonomic stress reactions in rats.