RESUMEN
A series of 31 arylboronic acids designed on the basis of the pharmacophore model for a variety of TRPV1 antagonists was prepared and tested on FAAH and TRPV1 channel. Four of them, that is, compounds 3c, 4a, 5a,b acted as dual FAAH/TRPV1 blockers with IC50 values between 0.56 and 8.11µM whereas ten others (compounds 1c,f-i, 2c-f, 4b) inhibited FAAH and activated/desensitized TRPV1.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Ácidos Borónicos/farmacología , Inhibidores Enzimáticos/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Amidohidrolasas/metabolismo , Ácidos Borónicos/síntesis química , Ácidos Borónicos/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Ligandos , Estructura Molecular , Relación Estructura-Actividad , Canales Catiónicos TRPV/metabolismoRESUMEN
A series of twenty resveratrol analogues was synthesized and tested on TRPA1 and TRPV1 channels. None was able to significantly modulate TRPV1 channels. Conversely, most of them exhibited remarkably higher TRPA1 modulating activity than resveratrol. Optimal potency was observed with ortho monoxygenated stilbenes 6 and 17.
Asunto(s)
Estilbenos/química , Canales Catiónicos TRPC/metabolismo , Animales , Calcio/metabolismo , Células HEK293 , Humanos , Concentración 50 Inhibidora , Transporte Iónico/efectos de los fármacos , Unión Proteica , Ratas , Resveratrol , Estilbenos/metabolismo , Estilbenos/farmacología , Canal Catiónico TRPA1 , Canales Catiónicos TRPC/química , Canales Catiónicos TRPC/genéticaRESUMEN
The pharmacological inhibition of anandamide (AEA) hydrolysis by fatty acid amide hydrolase (FAAH) attenuates pain in animal models of osteoarthritis (OA) but has failed in clinical trials. This may have occurred because AEA also activates transient receptor potential vanilloid type 1 (TRPV1), which contributes to pain development. Therefore, we investigated the effectiveness of the dual FAAH-TRPV1 blocker OMDM-198 in an MIA-model of osteoarthritic pain. We first investigated the MIA-induced model of OA by (1) characterizing the pain phenotype and degenerative changes within the joint using X-ray microtomography and (2) evaluating nerve injury and inflammation marker (ATF-3 and IL-6) expression in the lumbar dorsal root ganglia of osteoarthritic rats and differences in gene and protein expression of the cannabinoid CB1 receptors FAAH and TRPV1. Furthermore, we compared OMDM-198 with compounds acting exclusively on FAAH or TRPV1. Osteoarthritis was accompanied by the fragmentation of bone microstructure and destroyed cartilage. An increase of the mRNA levels of ATF3 and IL-6 and an upregulation of AEA receptors and FAAH in the dorsal root ganglia were observed. OMDM-198 showed antihyperalgesic effects in the OA model, which were comparable with those of a selective TRPV1 antagonist, SB-366,791, and a selective FAAH inhibitor, URB-597. The effect of OMDM-198 was attenuated by the CB1 receptor antagonist, AM-251, and by the nonpungent TRPV1 agonist, olvanil, suggesting its action as an "indirect" CB1 agonist and TRPV1 antagonist. These results suggest an innovative strategy for the treatment of OA, which may yield more satisfactory results than those obtained so far with selective FAAH inhibitors in human OA.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Carbamatos/administración & dosificación , Carbamatos/farmacología , Ganglios Espinales/metabolismo , Osteoartritis/fisiopatología , Dolor/tratamiento farmacológico , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/metabolismo , Factor de Transcripción Activador 3/genética , Factor de Transcripción Activador 3/metabolismo , Amidohidrolasas/genética , Amidohidrolasas/metabolismo , Anilidas/administración & dosificación , Anilidas/farmacología , Animales , Ácidos Araquidónicos/metabolismo , Benzamidas/farmacología , Capsaicina/análogos & derivados , Capsaicina/farmacología , Cinamatos/administración & dosificación , Cinamatos/farmacología , Modelos Animales de Enfermedad , Endocannabinoides/metabolismo , Ganglios Espinales/citología , Expresión Génica/efectos de los fármacos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/genética , Hiperalgesia/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Interleucina-6/genética , Interleucina-6/metabolismo , Vértebras Lumbares/citología , Masculino , Dolor/inmunología , Dolor/metabolismo , Manejo del Dolor/métodos , Dimensión del Dolor/métodos , Piperidinas/farmacología , Alcamidas Poliinsaturadas/metabolismo , Pirazoles/farmacología , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB1/metabolismo , Canales Catiónicos TRPV/agonistas , Canales Catiónicos TRPV/genéticaRESUMEN
A series of thirty-six geraniol, nerol, citronellol, geranylamine, and nerylamine derivatives was synthesized and tested on TRPA1, TRPM8, and TRPV1 channels. Most of them acted as strong modulators of TRPA1 channels with EC50 and/or IC50 values <1 µM. None was able to significantly activate TRPM8 channels, while thirteen of them behaved as 'true' TRPM8 antagonists. Little or no effect was generally observed on TRPV1 channels. Some of the compounds examined, that is, compounds 1d,g,n, 2c,d,h,i,o, 3b,e exhibited an appreciable selectivity for TRPA1 subtype.
Asunto(s)
Alcoholes , Monoterpenos/metabolismo , Canales de Potencial de Receptor Transitorio/antagonistas & inhibidores , HumanosRESUMEN
Following the recent identification of the naturally occurring 3-ylidene-4,5-dihydrophthalide ligustilide and its oxidation product dehydroligustilide as novel TRPA1 modulators, a series of seventeen 3-ylidenephthalides was synthesized and tested on TRPA1 and TRPM8 channels. Most of these compounds acted as strong modulators of the two channel types with EC50 and/or IC50 values distinctly lower than those of the reference compounds.
Asunto(s)
Benzofuranos/química , Canales Catiónicos TRPC/metabolismo , Canales Catiónicos TRPM/metabolismo , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , Animales , Benzofuranos/síntesis química , Benzofuranos/metabolismo , Células HEK293 , Humanos , Oxidación-Reducción , Unión Proteica , Ratas , Canal Catiónico TRPA1 , Canales Catiónicos TRPC/agonistas , Canales Catiónicos TRPC/antagonistas & inhibidores , Canales Catiónicos TRPM/agonistas , Canales Catiónicos TRPM/antagonistas & inhibidoresRESUMEN
We showed previously that inhibiting fatty acid amide hydrolase (FAAH), an endocannabinoid degrading enzyme, and transient receptor potential vanilloid type-1 (TRPV1) channels with the same molecule, the naturally occurring N-arachidonoyl-serotonin (AA-5-HT), produces more efficacious anti-nociceptive and anti-hyperalgesic actions than the targeting of FAAH or TRPV1 alone. We also reported the synthesis of some piperazinyl carbamates as "dual" FAAH inhibitors and either antagonists at TRPV1 or agonists/desensitizers of the transient receptor potential ankyrin type-1 (TRPA1) cannel, another target for analgesic drugs. We investigated here if two such compounds, the FAAH/TRPV1 blocker OMDM198 and the FAAH inhibitor/TRPA1 agonist, OMDM202, exert anti-nociceptive actions in the formalin test of pain in mice, and through what mechanism. Both compounds inhibited the second phase of the response to formalin, the effect being maximal at 3 mg/kg, i.p. Antagonism of CB1 or CB2 receptors with AM251 or AM630 (1 mg/kg, i.p.), respectively, reversed this effect. A TRPV1 agonist, palvanil (0.1 mg/kg, i.p.), also reversed the analgesic effect of OMDM198. OMDM202 action was also antagonized by a per se inactive dose of the selective TRPA1 blocker, AP-18 (0.05 mg/kg, i.p.), but not by a TRPV1 antagonist. AP-18 at higher doses (0.1-0.2 mg/kg) inhibited both the first and second phase of the formalin response. The effects of OMDM198 and OMDM202 were accompanied by elevation of anandamide levels in the spinal cord. OMDM198 (0.1-5.0 mg/kg, i.p.) also reversed carrageenan-induced oedema and thermal hyperalgesia in mice with efficacy similar to that of AA-5-HT. These data suggest that "dual" fatty acid amide hydrolase and transient receptor potential channel modulators should be clinically evaluated as novel analgesics.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Analgésicos/uso terapéutico , Carbamatos/uso terapéutico , Dolor/tratamiento farmacológico , Analgésicos/química , Animales , Ácidos Araquidónicos/análisis , Ácidos Araquidónicos/metabolismo , Carbamatos/química , Edema/tratamiento farmacológico , Edema/enzimología , Edema/metabolismo , Endocannabinoides/análisis , Endocannabinoides/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Dolor/enzimología , Dolor/metabolismo , Dimensión del Dolor/efectos de los fármacos , Alcamidas Poliinsaturadas/análisis , Alcamidas Poliinsaturadas/metabolismo , Canal Catiónico TRPA1 , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales de Potencial de Receptor Transitorio/agonistasRESUMEN
In the present study, we have further extended the structure-activity relationships for the tetrazolyl ureas class of compounds as potential FAAH and/or MAGL inhibitors, by replacing the dimethylamino group of the parent compounds 1 and 2 with bulkier groups or by introducing on the distal phenyl ring of 1 and 2 a selected set of substituents. Some of the new compounds (16, 20, 21, 25, and 28) inhibited FAAH potently (IC50 = 3.0-9.7 nM) and selectively (39- to more than 141-fold) over MAGL, while tetrazole 27 turned out to be a promising dual FAAH-MAGL inhibitor of potential therapeutic use. Covalent docking studies on FAAH indicated that the binding modes of tetrazoles 1-32 did not display a unique pattern. The ability of tetrazoles 1-32 to act as TRPV1 and TRPA1 modulators was also investigated.
Asunto(s)
Endocannabinoides/antagonistas & inhibidores , Endocannabinoides/metabolismo , Tetrazoles/química , Tetrazoles/farmacología , Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/química , Amidohidrolasas/metabolismo , Animales , Células COS , Canales de Calcio/metabolismo , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Células HEK293 , Humanos , Activación del Canal Iónico/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Monoacilglicerol Lipasas/antagonistas & inhibidores , Monoacilglicerol Lipasas/química , Monoacilglicerol Lipasas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Ratas , Relación Estructura-Actividad , Canal Catiónico TRPA1 , Canales Catiónicos TRPV/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo , Urea/química , Urea/farmacologíaRESUMEN
A series of twenty-five derivatives of tetrahydro-ß-carbolines 1-3 was synthesized and assayed on FAAH and TRPV1 and TRPA1 channels. Four carbamates, that is, 5a,c,e, and 9b inhibited FAAH with significant potency and interacted also effectively with TRPV1 and TRPA1 nociceptive receptors, while ureas 7b,d,f, and 8a,b were endowed with specific submicromolar TRPV1 modulating activities.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Carbolinas/química , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales de Potencial de Receptor Transitorio/antagonistas & inhibidores , Amidohidrolasas/metabolismo , Analgésicos/síntesis química , Analgésicos/química , Analgésicos/metabolismo , Canales de Calcio/metabolismo , Carbamatos/química , Carbolinas/síntesis química , Carbolinas/metabolismo , Humanos , Proteínas del Tejido Nervioso/metabolismo , Unión Proteica , Relación Estructura-Actividad , Canal Catiónico TRPA1 , Canales Catiónicos TRPV/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo , Urea/químicaRESUMEN
A series of thirty-three thymol, p-cymene-3-carboxylic acid, and 3-amino-p-cymene derivatives was synthesized and tested on TRPA1, TRPM8, and TRPV3 channels. Most of them acted as strong modulators of TRPA1, TRPM8, and TRPV3 channels with EC(50) and/or IC(50) values distinctly lower than those of thymol and related monoterpenoids. Some of the compounds examined, that is, 3c, 4e, f, 6b, and 8b exhibited an appreciable subtype-selectivity.
Asunto(s)
Timol/farmacología , Canales de Potencial de Receptor Transitorio/efectos de los fármacos , Animales , Línea Celular , Humanos , Ratas , Timol/químicaRESUMEN
In order to explore the structural determinants for the TRPV1 and TRPA1 agonist properties of gingerols, a series of nineteen analogues (1b-5) of racemic [6]-gingerol (1a) was synthesized and tested on TRPV1 and TRPA1 channels. The exploration of the structure-activity relationships, by modulating the three pharmacophoric regions of [6]-gingerol, led to the identification of some selective TRPV1 agonists/desensitizers of TRPV1 channels (3a, 3f, and 4) and of some full TRPA1 antagonists (2c, 2d, 3b, and 3d).
Asunto(s)
Catecoles/síntesis química , Alcoholes Grasos/síntesis química , Proteínas del Tejido Nervioso/agonistas , Canales Catiónicos TRPV/agonistas , Canales de Potencial de Receptor Transitorio/agonistas , Canales de Calcio , Catecoles/química , Catecoles/farmacología , Alcoholes Grasos/química , Alcoholes Grasos/farmacología , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Unión Proteica/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad , Canal Catiónico TRPA1 , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales de Potencial de Receptor Transitorio/antagonistas & inhibidoresRESUMEN
A series of twenty-two (-)-menthylamine derivatives was synthesized and tested on TRPM8, TRPV1, and TRPA1 channels. Five of the novel compounds, that is, 1d, 1f, 2b, 2c, and 2e behaved as potent TRPM8 antagonists with IC(50) values versus icilin and (-)-menthol between 20 nM and 0.7 microM, and were between 4- and approximately 150-fold selective versus TRPV1 and TRPA1 activation. Compound 1d also induced caspase 3/7 release in TRPM8-expressing LNCaP prostate carcinoma cells, but not in non-TRPM8 expressing DU-145 cells. Five other derivatives, that is, 1a, 1g, 1h, 2f, and 2h were slightly less potent than previous compounds but still relatively selective versus TRPV1 and TRPA1.
Asunto(s)
Antineoplásicos/química , Mentol/análogos & derivados , Canales Catiónicos TRPM/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular Tumoral , Humanos , Mentol/síntesis química , Mentol/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Canales Catiónicos TRPM/metabolismoRESUMEN
The evaluation of a series of piperazinyl carbamates and ureas, designed on the basis of previously reported TRPV1 antagonists and FAAH inhibitors, led to the identification of some 'dual-action' compounds targeting both FAAH and TRPV1 or TRPA1 receptors.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Carbamatos/síntesis química , Carbamatos/farmacología , Canales de Potencial de Receptor Transitorio/antagonistas & inhibidores , Urea/síntesis química , Urea/farmacología , Carbamatos/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ligandos , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Urea/químicaRESUMEN
The present investigations deal with the modeling of the peptide surrounding of [FeFe] hydrogenase using amine containing disulphides to simulate possible influences of the amino acid lysine (K237) on the electrochemical and electrocatalytic properties of biomimetic compounds based on [Fe2S2] moieties. Fe(3)(CO)(12) was reacted with Boc-4-amino-1,2-dithiolane, Boc-Adt-OMe (Adt=4-amino-1,2-dithiolane-4-carboxylic acid, Boc=tert-butoxycarbonyl) and Boc-Adp tert-butyl ester (Adp=(S)-2-amino-3-(1,2-dithiolan-4-yl)propionic acid) to elongate the Fecdots, three dots, centeredN distance in comparison to the well known [Fe(2){(SCH(2))(2)NR}(CO)(6)] model complexes. Efforts to deprotect the complexes containing Boc-4-amino-1,2-dithiolane with trifluoroacetic acid result in the formation of [Fe(3)(mu(3)-O)(mu-O(2)C(2)F(3))(6)(OC(4)H(8))(2)(H(2)O)]. The novel [2Fe2S] complexes are characterized using spectroscopic, electrochemical techniques and X-ray diffraction studies.
Asunto(s)
Biocatálisis , Dominio Catalítico , Hidrogenasas/química , Proteínas Hierro-Azufre/química , Modelos Moleculares , Cristalografía por Rayos X , Hidrogenasas/metabolismo , Proteínas Hierro-Azufre/metabolismo , Ligandos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Imitación Molecular , Estructura Molecular , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Although inhibitors of the enzymatic hydrolysis of the endocannabinoid 2-arachidonoylglycerol are available, they are either rather weak in vitro (IC(50)>30 microM) or their selectivity towards other proteins of the endocannabinoid system has not been tested. Here we describe the synthesis and activity in vitro and in vivo of a tetrahydrolipstatin analogue, OMDM169, as a potent inhibitor of 2-AG hydrolysis, capable of enhancing 2-AG levels and of exerting analgesic activity via indirect activation of cannabinoid receptors. OMDM169 exhibited 0.13 microM
Asunto(s)
Analgésicos/síntesis química , Analgésicos/farmacología , Ácidos Araquidónicos/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Formamidas/síntesis química , Formamidas/farmacología , Glicéridos/antagonistas & inhibidores , Propiolactona/análogos & derivados , Animales , Ácidos Araquidónicos/metabolismo , Células COS , Chlorocebus aethiops , Endocannabinoides , Glicéridos/metabolismo , Humanos , Hidrólisis/efectos de los fármacos , Concentración 50 Inhibidora , Lipoproteína Lipasa/metabolismo , Ratones , Monoacilglicerol Lipasas/metabolismo , Propiolactona/síntesis química , Propiolactona/farmacología , RatasRESUMEN
A series of 21 analogues of tetrahydrolipstatin (THL, 1) were synthesized and tested as inhibitors of the formation or hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG). Three of the novel compounds, i.e., 11, 13, and 15, inhibited 2-AG formation via the diacylglycerol lipase alpha (DAGLalpha) with IC 50 values lower than 50 nM (IC 50 of THL = 1 microM) and were between 23- and 375-fold selective vs 2-AG hydrolysis by monoacylglycerol lipase (MAGL) as well as vs cannabinoid CB 1 and CB 2 receptors and anandamide hydrolysis by fatty acid amide hydrolase (FAAH). Three other THL analogues, i.e., 14, 16, and 18, were slightly more potent than THL against DAGLalpha and appreciably selective vs MAGL, CB receptors, and FAAH (15-26-fold). One compound, i.e., 8, was a potent inhibitor of MAGL-like activity (IC 50 = 0.41 microM), and relatively ( approximately 7-fold) selective vs the other targets tested.
Asunto(s)
Ácidos Araquidónicos/metabolismo , Moduladores de Receptores de Cannabinoides/síntesis química , Moduladores de Receptores de Cannabinoides/farmacología , Endocannabinoides , Glicéridos/metabolismo , Lactonas/síntesis química , Lactonas/farmacología , Animales , Ácidos Araquidónicos/química , Moduladores de Receptores de Cannabinoides/química , Línea Celular Tumoral , Glicéridos/química , Concentración 50 Inhibidora , Lactonas/química , Ratones , Estructura Molecular , Orlistat , Relación Estructura-ActividadRESUMEN
A new series of 1,5- and 2,5-disubstituted tetrazoles have been synthesized and evaluated as inhibitors of anandamide cellular uptake. Some of them inhibit the uptake process with a relatively high potency (IC(50)=2.3-5.1microM) and selectively over other proteins involved in endocannabinoid action and metabolism.
Asunto(s)
Ácidos Araquidónicos/antagonistas & inhibidores , Alcamidas Poliinsaturadas/antagonistas & inhibidores , Tetrazoles/farmacología , Alquilación , Animales , Ácidos Araquidónicos/metabolismo , Transporte Biológico/efectos de los fármacos , Células COS/efectos de los fármacos , Línea Celular Tumoral/efectos de los fármacos , Chlorocebus aethiops , Endocannabinoides , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Modelos Químicos , Alcamidas Poliinsaturadas/metabolismo , Relación Estructura-Actividad , Tetrazoles/síntesis químicaRESUMEN
We have synthesized a series of 18 1,5- and 2,5-disubstituted carbamoyl tetrazoles, including LY2183240 (1) and LY2318912 (7), two compounds previously described as potent inhibitors of the cellular uptake of the endocannabinoid anandamide, and their regioisomers 2 and 8. We confirm that compound 1 is a potent inhibitor of both the cellular uptake and, like the other new compounds synthesized here, the enzymatic hydrolysis of anandamide. With the exception of 9, 12, 15, and the 2,5-regioisomer of LY2183240 2, the other compounds were all found to be weakly active or inactive on anandamide uptake. Several compounds also inhibited the enzymatic hydrolysis of the other main endocannabinoid, 2-arachidonoylglycerol, as well as its enzymatic release from sn-1-oleoyl-2-arachidonoyl-glycerol, at submicromolar concentrations. Four of the novel compounds, i.e. 3, 4, 17, and 18, inhibited anandamide hydrolysis potently (IC50=2.1-5.4nM) and selectively over all the other targets tested (IC50 >or= 10microM), thus representing new potentially useful tools for the inhibition of fatty acid amide hydrolase.
Asunto(s)
Moduladores de Receptores de Cannabinoides/antagonistas & inhibidores , Endocannabinoides , Tetrazoles/química , Tetrazoles/farmacología , Amidohidrolasas/antagonistas & inhibidores , Animales , Ácidos Araquidónicos/antagonistas & inhibidores , Ácidos Araquidónicos/metabolismo , Moduladores de Receptores de Cannabinoides/metabolismo , Línea Celular Tumoral , Glicéridos/antagonistas & inhibidores , Glicéridos/metabolismo , Compuestos Heterocíclicos con 1 Anillo/química , Compuestos Heterocíclicos con 1 Anillo/metabolismo , Compuestos Heterocíclicos con 1 Anillo/farmacología , Hidrólisis/efectos de los fármacos , Alcamidas Poliinsaturadas/antagonistas & inhibidores , Alcamidas Poliinsaturadas/metabolismo , Ratas , Estereoisomerismo , Tetrazoles/metabolismo , Urea/análogos & derivados , Urea/química , Urea/metabolismo , Urea/farmacologíaRESUMEN
N-arachidonoylserotonin (AA-5-HT, 1a) is an inhibitor of fatty acid amide hydrolase (FAAH) that acts also as an antagonist of transient receptor potential vanilloid-type 1 (TRPV1) channels and is analgesic in rodents. We modified the chemical structure of 1a with the aim of developing "hybrid" FAAH/TRPV1 blockers more potent than the parent compound or obtaining analogues with single activity at either of the two targets to study the mechanism of the analgesic action of 1a. Thirty-eight AA-5-HT analogues, containing a serotonin "head" bound to a variety of lipophilic moieties via amide, urea, or carbamate functionalities, were synthesized. Unlike 1a, most of the new compounds possessed activity at only one of the two considered targets. The amides 1b and 1c of alpha- and gamma-linolenic acid, however, showed "hybrid" activity similar to 1a. The carbamate 3f (OMDM106), although unable to antagonize TRPV1 receptors, was the most potent FAAH inhibitor in this study (IC50=0.5 microM). Compounds 3f and 1m (OMDM129), which exhibited activity at only FAAH or TRPV1, respectively, were 10-fold less potent than 1a at preventing formalin-induced hyperalgesia in mice.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Analgésicos/síntesis química , Ácidos Araquidónicos/síntesis química , Compuestos de Bifenilo/síntesis química , Carbamatos/síntesis química , Indoles/síntesis química , Dolor/tratamiento farmacológico , Serotonina/análogos & derivados , Canales Catiónicos TRPV/antagonistas & inhibidores , Analgésicos/química , Analgésicos/farmacología , Animales , Ácidos Araquidónicos/química , Ácidos Araquidónicos/metabolismo , Ácidos Araquidónicos/farmacología , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Encéfalo/enzimología , Calcio/metabolismo , Carbamatos/química , Carbamatos/farmacología , Línea Celular , Endocannabinoides , Humanos , Hidrólisis , Hiperalgesia/tratamiento farmacológico , Indoles/química , Indoles/farmacología , Ratones , Dimensión del Dolor , Alcamidas Poliinsaturadas/metabolismo , Ratas , Serotonina/síntesis química , Serotonina/química , Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
On the basis of the chemical structures of two previously developed metabolically stable and relatively potent inhibitors of anandamide uptake, OMDM-1,2, two series of potential covalent inhibitors of anandamide cellular reuptake, which might be used for the molecular characterization of the protein(s) involved in the membrane transport of endocannabinoids, have been designed and synthesized. Most of the compounds inhibited uptake to a varied extent and in a generally enantio-sensitive manner when co-incubated with [(14)C]anandamide, but only three of them, the photoactivatable 1a (OMDM-37), 1b (OMDM-39), and 8(Lo395), also produced a significant inhibition of uptake following the preincubation only of the cells, and this effect was significantly enhanced following UV exposure only in the case of 8. None of the new compounds inhibited [(14)C]anandamide hydrolysis with IC(50) < 50 microM, except for 1b.
Asunto(s)
Ácidos Araquidónicos/antagonistas & inhibidores , Ácidos Araquidónicos/síntesis química , Compuestos de Bencilo/síntesis química , Amidohidrolasas/metabolismo , Animales , Ácidos Araquidónicos/metabolismo , Ácidos Araquidónicos/farmacología , Ácidos Araquidónicos/efectos de la radiación , Compuestos de Bencilo/farmacología , Compuestos de Bencilo/efectos de la radiación , Transporte Biológico , Encéfalo/metabolismo , Línea Celular , Línea Celular Tumoral , Membrana Celular/metabolismo , Endocannabinoides , Proteínas de Transporte de Ácidos Grasos/metabolismo , Hidrólisis , Técnicas In Vitro , Alcamidas Poliinsaturadas , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Rayos UltravioletaRESUMEN
Several selective inhibitors of endocannabinoid inactivation via either the fatty acid amide hydrolase (FAAH) or the putative endocannabinoid transporter have been developed so far. Here, we have studied the effect in rats of a subchronic intraperitoneal treatment with three recently developed selective inhibitors of endocannabinoid uptake (VDM-11, UCM-707 and OMDM-2) or with a selective FAAH inhibitor (N-arachidonoyl-serotonin, AA-5-HT), on the brain levels of anandamide and 2-arachidonoylglycerol (2-AG) measured by means of isotope dilution LC-MS 1, 5 and 12 h after the last treatment. OMDM-2 was the most efficacious compound at enhancing the levels of anandamide at all time points, with a maximal effect (1.9-fold enhancement) after 5h. This compound also enhanced 2-AG levels by approximately 1.3-fold, but only 5 and 12h from administration. VDM-11 slightly, albeit significantly, enhanced anandamide levels (1.3-fold) only at 1h from administration and 2-AG levels (1.3-fold) only after 5h. Finally, UCM-707 only affected 2-AG levels (by two-fold) at only 1h from administration. FAAH inhibition by AA-5-HT significantly enhanced the levels of both anandamide (between 1.3- and 1.5-fold, maximal effect after 1 h) and 2-AG (between 1.3- and 1.6-fold, maximal effect after 12 h) at all time points. Brains from rats treated with AA-5-HT did never exhibit enhanced levels of serotonin, thus pointing to the metabolic stability of this FAAH inhibitor. These data indicate that: (1) the pharmacological effects reported so far for the four compounds under study in animal models of diseases may be due to enhancement of both anandamide and 2-AG levels; (2) 2-AG seems to need a longer time after the last administration in order to be augmented; (3) OMDM-2 and AA-5-HT should be regarded as enhancers of endocannabinoid levels suitable for use in vivo.