RESUMEN
Phytocannabinoids, such as the principal bioactive component of marijuana, delta9-tetrahydrocannabinol, have been used for thousands of years for medical and recreational purposes. delta9-Tetrahydrocannabinol and endogenous cannabinoids (e.g., anandamide) initiate their agonist properties by stimulating the cannabinoid family of G protein-coupled receptors (CB1 and CB2). The biosynthesis and physiology of anandamide is well understood, but its mechanism of uptake (resulting in signal termination by fatty acid amide hydrolase) has been elusive. Mounting evidence points to the existence of a specific anandamide transport protein; however, no direct evidence for this protein has been provided. Here, we use a potent, competitive small molecule inhibitor of anandamide uptake (LY2318912, IC50 7.27 +/- 0.510 nM) to identify a high-affinity, saturable anandamide transporter binding site (LY2318912; K(d) = 7.62 +/- 1.18 nM, B(max) = 31.6 +/- 1.80 fmol/mg protein) that is distinct from fatty acid amide hydrolase. Systemic administration of the inhibitor into rodents elevates anandamide levels 5-fold in the brain and demonstrates efficacy in the formalin paw-licking model of persistent pain with no obvious adverse effects on motor function. Identification of the anandamide transporter binding site resolves a missing mechanistic link in endocannabinoid signaling, and in vivo results suggest that endocannabinoid transporter antagonists may provide a strategy for positive modulation of cannabinoid receptors.
Asunto(s)
Cannabinoides/metabolismo , Animales , Sitios de Unión/efectos de los fármacos , Transporte Biológico/efectos de los fármacos , Línea Celular , Humanos , Estructura Molecular , Ratas , Tetrazoles/química , Tetrazoles/farmacologíaRESUMEN
Glutamatergic hyperactivity is implicated migraine pathogenesis. Also, LY293558, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA) receptor antagonist, is effective in preclinical models of migraine. We therefore tested LY293558 in acute migraine. We conducted a randomized, triple-blind, parallel-group, double-dummy, multicentre trial of 1.2 mg/kg intravenous (IV) LY293558, 6 mg subcutaneous (SC) sumatriptan, or placebo in the treatment of acute migraine. The primary efficacy variable was the headache response rate, i.e. headache score improvement from moderate/severe at baseline to mild/none at 2 h. Of 45 enrolled patients, 44 patients (20M:24F; mean age +/- SD = 40 +/- 9 years) completed the study. Response rates were 69% for LY293558 (P = 0.017 vs. placebo), 86% for sumatriptan (P < 0.01 vs. placebo) and 25% for placebo. LY293558 and sumatriptan were superior to placebo (P < 0.01 for all comparisons) on all other measures of improvement in pain and migraine associated symptoms. Fifteen percent of patients who took LY293558 reported adverse events (AEs) (n = 2; one mild, one severe). Fifty-three percent of patients who took sumatriptan (n = 8; seven mild, one moderate) and 31% of those who received placebo reported AEs (n = 5; four mild, one severe). The efficacy and safety results of LY293558 in this small migraine proof of concept trial, together with supportive preclinical data, provide evidence for a potential role of nonvasoactive AMPA/KA antagonists in treating migraine. Larger trials are needed to further test the hypothesis.
Asunto(s)
Isoquinolinas/uso terapéutico , Trastornos Migrañosos/tratamiento farmacológico , Receptores AMPA/antagonistas & inhibidores , Receptores de Ácido Kaínico/antagonistas & inhibidores , Tetrazoles/uso terapéutico , Enfermedad Aguda , Adulto , Análisis de Varianza , Distribución de Chi-Cuadrado , Femenino , Humanos , Isoquinolinas/farmacología , Masculino , Persona de Mediana Edad , Trastornos Migrañosos/metabolismo , Receptores AMPA/metabolismo , Receptores de Ácido Kaínico/metabolismo , Tetrazoles/farmacologíaRESUMEN
Serotonin-1F receptor (5-HT1F) agonists may relieve acute migraine without vasoconstriction. We conducted a review of preclinical and clinical data that assessed the potential link between migraine and 5-HT1F activation. (i) A high correlation exists between the potency of various 5-HT1 receptor agonists in the guinea pig dural plasma protein extravasation assay and their 5-HT1F receptor binding affinity. (ii) 5-HT1F receptors are on the trigeminal system, and may participate in blocking migraine pain transmission through the trigeminal ganglion and nucleus caudalis. (iii) 5-HT1F receptors are located on glutamate-containing neurones and their activation might inhibit glutamate release; glutamate excess may play a role in migraine. (iv) Selective 5-HT1F receptor agonists (LY334370; LY344864) are effective in preclinical migraine models and are non-vasoconstrictive. (v) LY334370 is effective in acute migraine, and does not cause any symptoms/signs of coronary vasoconstriction. Preclinical experiments and clinical observations argue for a role of selective 5-HT1F agonists in migraine.
Asunto(s)
Trastornos Migrañosos/tratamiento farmacológico , Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/uso terapéutico , Enfermedad Aguda , Animales , Ensayos Clínicos como Asunto/estadística & datos numéricos , Humanos , Trastornos Migrañosos/metabolismo , Receptor de Serotonina 5-HT1FRESUMEN
The compound m-chlorophenylpiperazine (mCPP), which is known to trigger migraine-like head pain in some subjects, was evaluated for its ability to induce dural plasma protein extravasation (PPE) in guinea pigs. Intravenous mCPP dose-dependently increased PPE. This effect was inhibited by non-selective 5-HT2 receptor antagonists (methysergide, LY53857, LY215840), by a peripherally restricted 5-HT2 receptor antagonist (xylamidine) and by a 5-HT2B selective receptor antagonist (LY202146). These data suggests that peripheral 5-HT2B receptors mediate mCPP-induced PPE. The nitric oxide synthase inhibitor L-NAME and 5-HT1 agonist sumatriptan also blocked mCPP-induced PPE, suggesting a role for nitric oxide (NO) and the trigeminal system, respectively. NO release has been linked to activation of the 5-HT2B receptor on the vascular endothelium. However, LY202146 did not block PPE induced by electrical stimulation of the trigeminal ganglion. These data are consistent with activation of peripheral 5-HT2B receptors initiating PPE and the theory that selective 5-HT2B antagonists might be effective prophylactic therapies for migraine.
Asunto(s)
Proteínas Sanguíneas/metabolismo , Duramadre/efectos de los fármacos , Duramadre/metabolismo , Óxido Nítrico/metabolismo , Piperazinas/administración & dosificación , Receptores de Serotonina/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Duramadre/citología , Estimulación Eléctrica , Cobayas , Inyecciones Intravenosas , Masculino , Trastornos Migrañosos/inducido químicamente , Trastornos Migrañosos/metabolismo , Receptor de Serotonina 5-HT2B , Valores de ReferenciaRESUMEN
Parkinson's disease is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. We now report that minocycline, a semisynthetic tetracycline, recently shown to have neuroprotective effects in animal models of stroke/ischemic injury and Huntington's disease, prevents nigrostriatal dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Minocycline treatment also blocked dopamine depletion in the striatum as well as in the nucleus accumbens after MPTP administration. The neuroprotective effect of minocycline is associated with marked reductions in inducible NO synthase (iNOS) and caspase 1 expression. In vitro studies using primary cultures of mesencephalic and cerebellar granule neurons (CGN) and/or glia demonstrate that minocycline inhibits both 1-methyl-4-phenylpyridinium (MPP(+))-mediated iNOS expression and NO-induced neurotoxicity, but MPP(+)-induced neurotoxicity is inhibited only in the presence of glia. Further, minocycline also inhibits NO-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) in CGN and the p38 MAPK inhibitor, SB203580, blocks NO toxicity of CGN. Our results suggest that minocycline blocks MPTP neurotoxicity in vivo by indirectly inhibiting MPTP/MPP(+)-induced glial iNOS expression and/or directly inhibiting NO-induced neurotoxicity, most likely by inhibiting the phosphorylation of p38 MAPK. Thus, NO appears to play an important role in MPTP neurotoxicity. Neuroprotective tetracyclines may be effective in preventing or slowing the progression of Parkinson's and other neurodegenerative diseases.
Asunto(s)
Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/prevención & control , Minociclina/farmacología , Degeneración Nerviosa/prevención & control , Fármacos Neuroprotectores/farmacología , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/prevención & control , Animales , Caspasa 1/metabolismo , Células Cultivadas , Dopamina/metabolismo , Humanos , Imidazoles/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Monoaminooxidasa/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II , Trastornos Parkinsonianos/inducido químicamente , Fosforilación , Piridinas/farmacología , Corteza Visual/efectos de los fármacos , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
Recent studies have demonstrated that selective 5-HT(1F) receptor agonists inhibit neurogenic dural inflammation, a model of migraine headache, indicating that these compounds may be effective therapies for the treatment of migraine pain. This communication describes the synthesis and discovery of a novel compound, N-[3-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl]-4-fluorobenzamide (4), which possesses high binding affinity and selectivity at the 5-HT(1F) receptor relative to more than 40 other serotonergic and nonserotonergic receptors examined.
Asunto(s)
Benzamidas/síntesis química , Indoles/síntesis química , Trastornos Migrañosos/tratamiento farmacológico , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/síntesis química , Animales , Benzamidas/química , Benzamidas/metabolismo , Benzamidas/farmacología , Línea Celular , Duramadre/efectos de los fármacos , Cobayas , Humanos , Técnicas In Vitro , Indoles/química , Indoles/metabolismo , Indoles/farmacología , Inflamación , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Conejos , Ratas , Receptores de Neurotransmisores/metabolismo , Receptores de Serotonina/metabolismo , Vena Safena/efectos de los fármacos , Vena Safena/fisiología , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Relación Estructura-Actividad , Receptor de Serotonina 5-HT1FRESUMEN
BACKGROUND: Triptans (5-HT(1B/1D) receptor agonists) are effective drugs for acute migraine, but the side-effect of coronary vasoconstriction restricts their use in patients who are at risk of coronary artery disease. We have studied the efficacy of LY334370, a selective serotonin 1F (5-HT(1F)) receptor agonist with preclinical efficacy and no vasoconstriction, for migraine relief. METHODS: We gave LY334370 (20, 60, or 200 mg) or placebo to 99 outpatients with moderate or severe migraine headaches in a double blind, parallel group study. We measured efficacy by sustained response, response at 2 h, pain free at 2 h, and sustained pain free. FINDINGS: The proportions of patients with defined endpoints for placebo and LY334370 20, 60, and 200 mg, respectively, were: sustained response, two of 26 (8%), three of 22 (14%), 11 of 30 (37%), and 11 of 21 (52%) (dose response p<0.001); response, five of 26 (19%), four of 22 (18%), 15 of 30 (50%), and 15 of 21 (71%) (p<0.001); pain free, one of 26 (4%), none of 22, eight of 30 (27%), and eight of 21 (38%) (p=0.001); sustained pain free, one of 26 (4%), none of 22, seven of 30 (23%), and seven of 21 (33%) (p=0.002); recurrence rates, one of five (20%), none of four, four of 15 (27%), and three of 15 (20%). More patients given LY334370 than placebo reported asthenia, somnolence, and dizziness. INTERPRETATION: Our findings show that LY334370 is effective in treatment of acute migraine through selective trigeminovascular neuronal inhibition.
Asunto(s)
Benzamidas/uso terapéutico , Indoles/uso terapéutico , Trastornos Migrañosos/tratamiento farmacológico , Agonistas de Receptores de Serotonina/uso terapéutico , Adulto , Benzamidas/efectos adversos , Benzamidas/sangre , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Indoles/efectos adversos , Indoles/sangre , Masculino , Persona de Mediana Edad , Agonistas de Receptores de Serotonina/efectos adversos , Agonistas de Receptores de Serotonina/sangreRESUMEN
Lanepitant, a potent non-peptide neurokinin-1 receptor antagonist, inhibits neurogenic dural inflammation, and may have a role in migraine therapy. This study evaluated the effect of lanepitant taken daily for migraine prevention. Patients with migraine headaches with and without aura by International Headache Society classification criteria were enrolled in a 12-week double-blind, parallel design study comparing the effect of 200 mg qd lanepitant (n = 42) and placebo (n = 42) on reduction of migraine frequency. The primary outcome measure was response rate, i.e. the proportion of patients with a 50% reduction in days of headache. Of the 84 patients enrolled, 90.5% were female. The endpoint response rate for lanepitant-treated patients (41.0%) was not statistically significantly (P = 0.065) greater than that for placebo-treated patients (22.0%). No efficacy variables differed significantly between treatments, except for response rates at month 3 (P = 0.045). Higher plasma concentrations were no more effective than lower concentrations. In this study lanepitant was not effective in preventing migraine, but was well tolerated. These results do not support a role for NK-1 antagonism in migraine prevention.
Asunto(s)
Indoles/administración & dosificación , Trastornos Migrañosos/prevención & control , Antagonistas del Receptor de Neuroquinina-1 , Piperidinas/administración & dosificación , Adulto , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Indoles/efectos adversos , Masculino , Persona de Mediana Edad , Piperidinas/efectos adversos , Recurrencia , Resultado del TratamientoRESUMEN
The cause of migraine pain is controversial. One recently proposed theory is that migraine pain may originate from inflammation of the meninges, particularly the dural membranes that surround the brain. This theory proposes that, during a migraine, there is an idiopathic activation of trigeminal sensory afferents, resulting in nociceptive transmission to the CNS as well as the release of pro-inflammatory substances in the periphery, particularly the dura. Dural inflammation is thought to lower the nociceptive threshold of dural afferents and facilitate nociceptive transmission to the central nervous system. In the procedure described in this unit, trigeminal sensory afferents are activated by electrically stimulating the trigeminal ganglion. This stimulation causes trigeminal peripheral sensory afferents to depolarize, inflammatory substances to be released from these afferents, and dural inflammation to appear. Dural inflammation is quantified by measuring plasma protein extravasation. The basic protocol describes this model in rats, and the alternate protocol describes the analogous procedure in guinea pigs.
Asunto(s)
Vías Aferentes/fisiopatología , Síndrome de Fuga Capilar/etiología , Modelos Animales de Enfermedad , Duramadre/patología , Mediadores de Inflamación/análisis , Meningitis/fisiopatología , Trastornos Migrañosos/fisiopatología , Animales , Proteínas Sanguíneas/análisis , Síndrome de Fuga Capilar/fisiopatología , Duramadre/irrigación sanguínea , Estimulación Eléctrica/efectos adversos , Espacio Extracelular , Cobayas , Masculino , Potenciales de la Membrana , Meningitis/etiología , Microscopía Fluorescente , Ratas , Ratas Wistar , Técnicas Estereotáxicas , Ganglio del TrigéminoAsunto(s)
Diseño de Fármacos , Serotoninérgicos , Serotonina , Animales , Humanos , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/etiología , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/etiología , Neurotransmisores , Receptores de Serotonina/clasificación , Receptores de Serotonina/fisiología , Serotonina/fisiología , Serotoninérgicos/uso terapéuticoRESUMEN
To determine the potency and efficacy of 5-HT1F receptor ligands, a [35S]GTPgammaS binding assay was developed and optimized for the human 5-HT1F receptor. Compounds which are known to be effective in the abortive treatment of migraine were tested for efficacy and potency in this assay. Naratriptan, sumatriptan, zolmitriptan, and rizatriptan all had agonist activity. The 5-HT1F receptor ligand LY334370 (4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]-benzamide) was the most potent compound tested with an EC50 of 2.13 +/- 0.15 nM. LY302148 (5-fluoro-3-[1-[2-(1-methyl-1H-pyrazol-4-yl)ethyl]-4-piperidinyl]-1H-ind ole), methysergide, LY306258 (3-dimethylamino-2,3,4,9-tetrahydro-1H-carbazol-6-ol), dihydroergotamine (DHE), L-694,247 and CP-122,288 were also investigated for potency and efficacy. There was a statistically significant correlation between the pEC50 for the stimulation of [35S]GTPgammaS binding and the pID50 for the inhibition of trigeminal nerve-stimulated dural plasma protein extravasation in the guinea pig. In the course of these studies, it was found that the purportedly selective 5-HT1D receptor antagonist GR127935 inhibited 5-HT1F receptor-stimulated [35S]GTPgammaS binding with a Ki of 39.6 +/- 9.5 nM. These studies demonstrate that 5-HT1F receptor-mediated stimulation of [35S]GTPgammaS binding in a clonal cell system is a reproducible, high throughput assay that is predictive of an in vivo model of 5-HT1F receptor activation.
Asunto(s)
Proteínas Sanguíneas/metabolismo , Duramadre/efectos de los fármacos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Receptores de Serotonina/metabolismo , Animales , Permeabilidad Capilar , Relación Dosis-Respuesta a Droga , Duramadre/metabolismo , Cobayas , Humanos , Ratones , Proteínas Recombinantes/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Radioisótopos de Azufre , Nervio Trigémino/fisiología , Receptor de Serotonina 5-HT1FRESUMEN
Neurogenic dural inflammation has been proposed as a source of pain during migraine. Unilateral electrical stimulation of the trigeminal ganglion causes the ipsilateral release of inflammatory neuropeptides and subsequent dural plasma protein extravasation, a component of neurogenic inflammation. We measured the amount of protein leaking into the dural tissue of guinea pigs following trigeminal ganglion stimulation by exploiting the complexation reaction of endogenous proteins with the fluorescent dye Evans Blue, instead of utilizing exogenous radiolabeled albumin as commonly done in the literature. The amount of Evans Blue trapped in dural tissue following electrical stimulation of the trigeminal ganglion was measured using a fluorescence microscope equipped with a spectrophotometer. This method utilized multiple measurements on each dura sample which resulted in very precise values using a small number of animals per point (n = 3). Sumatriptan and CP-122,288 were found to dose-dependently prevent neurogenic dural extravasation. The potencies of CP-122,288 and sumatriptan were found to be similar to those reported in the literature when similar experimental protocols were used.
Asunto(s)
Duramadre/metabolismo , Extravasación de Materiales Terapéuticos y Diagnósticos/metabolismo , Fluorescencia , Proteínas/análisis , Proteínas/metabolismo , Ganglio del Trigémino/fisiología , Animales , Transporte Biológico/efectos de los fármacos , Estimulación Eléctrica , Azul de Evans/administración & dosificación , Cobayas , Inflamación/etiología , Inflamación/metabolismo , Inyecciones Intravenosas , Masculino , Microscopía Fluorescente , Microespectrofotometría , Trastornos Migrañosos/etiología , Unión Proteica , Pirrolidinas/administración & dosificación , Pirrolidinas/farmacología , Sumatriptán/administración & dosificación , Sumatriptán/análogos & derivados , Sumatriptán/farmacologíaRESUMEN
A role for serotonin in migraine has been supported by changes in circulating levels of serotonin and its metabolites during the phases of a migraine attack, along with the ability of serotonin-releasing agents to induce migraine-like symptoms. The development of serotonin receptor agonists with efficacy in the clinic for the alleviation of migraine pain further implicates serotonin as a key molecule in migraine. Several theories regarding the etiology of migraine have been proposed. The vasodilatory theory of migraine suggested that extracranial arterial dilation during an attack was related to migraine pain; a theory supported when vasoconstrictors such as sumatriptan alleviated migraine pain. The neurological theory of migraine proposed that migraine resulted from abnormal firing in brain neurons. Cortical spreading depression, one facet of the neurological theory, could explain the prodrome of migraine. The neurogenic dural inflammation theory of migraine supposed that the dural membrane surrounding the brain became inflamed and hypersensitive due to release of neuropeptides from primary sensory nerve terminals. Substance P, calcitonin gene related peptide and nitric oxide are all though to play a role in the dural inflammatory cascade. Animal models of migraine have been utilized to study the physiology of migraine and develop new pharmaceutical therapies. One model measures the shunting of blood to arteriovenous anastomoses based on a proposal that migraine primarily involves cranial arteriovenous vasodilation. Another model utilizes electrical stimulation of the trigeminal ganglion to induce neurogenic dural inflammation quantified by the resulting extravasation of proteins. Pharmacological agents such as meta-chlorophenylpiperazine (mCPP) and nitroglycerin have also been used to induce dural extravasation in animals. Both compounds also induce migraine attacks in individuals with a history of migraine. In addition, Fos, a protein produced by activation of the c-fos gene, has been measured as an index of migraine-like pain transmission to the CNS following chemical or electrical stimulation of the trigeminal nerve. A role for serotonin in migraine is further supported by the efficacy of serotonin receptor ligands. Sumatriptan is an agonist at 5-HT1D and 5-HT1B receptor subtypes, and effective in treating migraine pain and associated symptoms. Recently, selective 5-HT1F agonists have been proposed for the treatment of migraine, without the side effects associated with the present 5-HT1D and 5-HT1B receptor agonists. A role for 5-HT2B receptors has also been suggested the initiation of migraine, supporting use of selective 5-HT2B receptor antagonists in migraine. Thus, agents that modulate 5-HT1B, 5-HT1D, 5-HT1F and 5-HT2B receptors either have or may have clinical utility in the therapy of migraine headache.
Asunto(s)
Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/metabolismo , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/uso terapéutico , Serotonina/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/uso terapéuticoRESUMEN
Canine and rabbit vascular contractile responses to serotonergic agonists have been used to predict antimigraine efficacy for several antimigraine agents, including sumatriptan. The purpose of the present study was to establish the assumed predictive value of contractile responses in canine and rabbit saphenous veins to contractile efficacy for a series of agonists in human cerebral and coronary arteries and to understand better the receptors mediating such responses. The canine and rabbit saphenous veins contracted similarly (both qualitatively and quantitatively) to a series of structurally diverse serotonergic agonists, suggesting that the receptors mediating serotonin-induced contractility in these tissues were similar. In addition, the contractile potency (estimated as EC50 values) for these structurally diverse serotonergic agonists in either the rabbit or canine saphenous vein significantly correlated with contractile potency for these agonists in human cerebral arteries. Thus, to the extent that contractile responsiveness of human cerebral arteries may predict antimigraine agents, contractile responses of the rabbit and/or canine saphenous vein may be useful surrogates for antimigraine efficacy. In addition, the contractile potency for this series of serotonergic agonists in the rabbit or canine saphenous vein significantly correlated with contractile potency of these agonists in human coronary arteries. These data suggest that the use of the saphenous vein to identify potent vasoconstrictors will also reveal agents capable of contracting human coronary arteries, a liability for using this approach to evaluate promising antimigraine therapies.
Asunto(s)
Arterias Cerebrales/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , Trastornos Migrañosos/tratamiento farmacológico , Receptores de Serotonina/efectos de los fármacos , Vena Safena/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Animales , Arterias Cerebrales/metabolismo , Vasos Coronarios/metabolismo , Perros , Evaluación Preclínica de Medicamentos , Humanos , Conejos , Vena Safena/metabolismoRESUMEN
The serotonin (5-HT) receptor subtype mediating inhibition of neurogenic dural inflammation in guinea pigs was investigated using a series of serotonin agonists with differing affinities for the 5-HT1B, 5-HT1D and 5-HT1F receptors. When agonist potencies for inhibiting neurogenic inflammation were compared with affinities for these receptor subtypes, a significant positive correlation was seen only with the 5-HT1F receptor. The potency of agonists in inhibiting adenylate cyclase in cells transfected with human 5-HT1F receptor was also highly correlated with their potency in the animal model of migraine. In situ hybridization demonstrated 5-HT1F receptor mRNA in guinea pig trigeminal ganglion neurons. These data suggest that the 5-HT1F receptor is a rational target for migraine therapeutics.
Asunto(s)
Benzamidas/farmacología , Carbazoles/farmacología , Indoles/farmacología , Pirazoles/farmacología , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Ganglio del Trigémino/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Cobayas , Hibridación in Situ , Inflamación/tratamiento farmacológico , Masculino , Piperidinas/farmacología , ARN Mensajero/metabolismo , Conejos , Triptaminas , Receptor de Serotonina 5-HT1FRESUMEN
LY344864 is a selective receptor agonist with an affinity of 6 nM (Ki) at the recently cloned 5-HT1F receptor. It possesses little affinity for the 56 other serotonergic and non-serotonergic neuronal binding sites examined. When examined for its ability to inhibit forskolin-induced cyclic AMP accumulation in cells stably transfected with human 5-HT1F receptors, LY344864 was shown to be a full agonist producing an effect similar in magnitude to serotonin itself. After an intravenous dose of 1 mg/kg, rat plasma LY344864 levels declined with time whereas brain cortex levels remained relatively constant for the first 6 hours after injection. Oral and intravenous LY344864 administration potently inhibited dural protein extravasation caused by electrical stimulation of the trigeminal ganglion in rats. Taken together, these data demonstrate that LY344864 is a selective 5-HT1F receptor agonist that can be used to explore both the in vitro and in vivo functions of this receptor.
Asunto(s)
Encéfalo/metabolismo , Carbazoles/farmacología , Duramadre/patología , Fluorobencenos/farmacología , Trastornos Migrañosos/metabolismo , Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Animales , Carbazoles/sangre , Carbazoles/farmacocinética , Modelos Animales de Enfermedad , Duramadre/metabolismo , Fluorobencenos/sangre , Fluorobencenos/farmacocinética , Humanos , Inflamación , Masculino , Trastornos Migrañosos/patología , Unión Proteica , Ratas , Ratas Endogámicas F344 , Proteínas Recombinantes/metabolismo , Agonistas de Receptores de Serotonina/sangre , Agonistas de Receptores de Serotonina/farmacocinética , Receptor de Serotonina 5-HT1FRESUMEN
LY303870 is a competitive, high affinity NK-1 receptor antagonist. It was tested in the trigeminal stimulation-induced neurogenic dural inflammation model of migraine. The neurogenic inflammation theory of migraine pain proposes that substance P, acting through NK-1 receptors, causes dural inflammation which enhances migraine pain. LY303870 administration potently inhibited neurogenic dural inflammation as measured by plasma protein extravasation caused by electrical stimulation of the trigeminal ganglion in guinea pigs. It was active in this model when administered via intravenous, oral or inhalation routes. LY306155, the enantiomer of LY303870 with lower affinity for the NK-1 receptor, was much less potent than LY303870 in this model. LY303870, at oral doses of 1, 10 and 100 microg/kg, produced a long, dose-dependent inhibition of dural inflammation, demonstrating a suitable duration of action for a potential use in acute migraine and migraine prophylaxis.
Asunto(s)
Indoles/farmacología , Trastornos Migrañosos/metabolismo , Antagonistas del Receptor de Neuroquinina-1 , Piperidinas/farmacología , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Duramadre/efectos de los fármacos , Duramadre/metabolismo , Estimulación Eléctrica , Cobayas , Masculino , Estereoisomerismo , Sumatriptán/farmacologíaRESUMEN
Early structure-activity studies on racemic tryptophan ester and amide NK-1 antagonists 5-7 led to the discovery that the potency of the series could be markedly increased by moving the carbonyl function in these molecules to an off-chain position as in the 3-aryl-1,2-diacetamidopropane 9. Further medicinal chemistry incorporating this change resulted in the discovery of a novel series of highly potent aryl amino acid derived NK-1 antagonists of the R stereoisomeric series (IC50's = 100 pM to > 5 microM). Compounds in this series were shown to be competitive antagonists using an in vitro NK-1 smooth muscle assay, and this data correlated well with observed human NK-1 binding affinities. Two of these agents, (R)-25 and (R)-32, blocked intrathecal NK-1 agonist-driven [Ac-[Arg6,Sar9,Met(O2)11]- substance P 6-11 (Ac-Sar9)] nociceptive behavior in mice. Both compounds potently blocked the neurogenic dural inflammation following trigeminal ganglion stimulation in the guinea pig after intravenous administration. Further, upon oral administration in this model, (R)-32 was observed to be very potent (ID50 = 91 ng/kg) and have a long duration of action (> 8 h at 1 micrograms/kg). Compound (R)-32, designated LY303870, is currently under clinical development as an NK-1 antagonist with a long duration of action.
Asunto(s)
Amidas/farmacología , Ésteres/farmacología , Antagonistas del Receptor de Neuroquinina-1 , Amidas/química , Analgésicos/química , Analgésicos/farmacología , Animales , Estimulación Eléctrica , Ésteres/química , Cobayas , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Ratones , Ratas , Especificidad de la Especie , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
During 30 minutes of global forebrain ischemia in rats, striatal intracellular levels of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) increase at the same time extracellular levels, measured by microdialysis, decrease. If DOPAC and HVA were free to diffuse out of cells, these changes in opposite directions should not occur. These data support the theory that a membrane potential-dependent active transport system is required for DOPAC and HVA to leave striatal cells. During ischemia and subsequent to ATP depletion, neurons and glia depolarize and active transport systems fail. DOPAC and HVA, which are still being produced inside neurons and possibly glia, can not be transported out of these cells and accumulate intracellularly.
Asunto(s)
Ácido 3,4-Dihidroxifenilacético/metabolismo , Isquemia Encefálica/metabolismo , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Ácido Homovanílico/metabolismo , Animales , Transporte Biológico Activo , Cuerpo Estriado/irrigación sanguínea , Dopamina/análogos & derivados , Masculino , Potenciales de la Membrana , Ratas , Ratas WistarRESUMEN
Toxic reactive oxygen species have been implicated as important mediators of tissue injury after reperfusion of ischemic organs. When rats are subject to 30 min global forebrain ischemia, 24 h following this insult, there is substantial loss of medium-sized neurones as revealed by histological sectioning of the striatal region of the forebrain. The goal of this study was to utilize microdialysis to directly measure one of the more stable intermediates of reduced molecular oxygen, H2O2 in the rat striatum following 4-vessel occlusion and reperfusion, and to correlate these levels with H2O2 toxicity to neurones grown in culture. A significant rise in striatal H2O2 levels was observed for about 1 h during reperfusion, amounting to an increase of approximately 100 microM at the peak. In control experiments where the dialysis probe was embedded in cortical regions surrounding the striatum (where there is no neuronal loss due to the ischemic episode), there was no measurable increase in tissue H2O2 levels. H2O2 has been previously shown to be neurotoxic to PC12 cells as well as rat primary hippocampal neurones at comparable concentrations striatal neurones experience during reperfusion. We demonstrate that H2O2 is also neurotoxic to the human cortical neuronal cell line, HCN-1A. These experiments establish an important link between oxidant generation and neuronal loss in this tissue following global forebrain ischemia.