The Experts below are selected from a list of 1992 Experts worldwide ranked by ideXlab platform
Carlo Alberto Maggi - One of the best experts on this subject based on the ideXlab platform.
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tachykinin NK2 Receptor Antagonists for the treatment of irritable bowel syndrome
British Journal of Pharmacology, 2004Co-Authors: Alessandro Lecci, Angela Capriati, Carlo Alberto MaggiAbstract:Tachykinin NK2 Receptors are expressed in the gastrointestinal tract of both laboratory animals and humans. Experimental data indicate a role for these Receptors in the regulation of intestinal motor functions (both excitatory and inhibitory), secretions, inflammation and visceral sensitivity. In particular, NK2 Receptor stimulation inhibits intestinal motility by activating sympathetic extrinsic pathways or NANC intramural inhibitory components, whereas a modulatory effect on cholinergic nerves or a direct effect on smooth muscle account for the NK2 Receptor-mediated increase in intestinal motility. Accordingly, selective NK2 Receptor Antagonists can reactivate inhibited motility or decrease inflammation- or stress-associated hypermotility. Intraluminal secretion of water is increased by NK2 Receptor agonists via a direct effect on epithelial cells, and this mechanism is active in models of diarrhoea since selective Antagonists reverse the increase in faecal water content in these models. Hyperalgesia in response to intraluminal volume signals is possibly mediated through the stimulation of NK2 Receptors located on peripheral branches of primary afferent neurones. NK2 Receptor Antagonists reduce the hyper-responsiveness that occurs following intestinal inflammation or application of stressful stimuli to animals. Likewise, NK2 Receptor Antagonists reduce intestinal tissue damage induced by chemical irritation of the intestinal wall or lumen. In healthy volunteers, the selective NK2 antagonist nepadutant reduced the motility-stimulating effects and irritable bowel syndrome-like symptoms triggered by intravenous infusion of neurokinin A, and displayed other characteristics that could support its use in patients. It is concluded that blockade of peripheral tachykinin NK2 Receptors should be considered as a viable mechanism for decreasing the painful symptoms and altered bowel habits of irritable bowel syndrome patients.
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effect of nepadutant a neurokinin 2 tachykinin Receptor antagonist on immediate early gene expression after trinitrobenzenesulfonic acid induced colitis in the rat
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Lori A Birder, Susanna Kiss, William C De Groat, Alessandro Lecci, Carlo Alberto MaggiAbstract:Tachykinins have been implicated in inflammatory responses such as those occurring in inflammatory bowel disease. Accordingly, we investigated the effect of a selective neurokinin (NK) 2 Receptor antagonist, nepadutant, on proto-oncogene expression in the L6-S1 spinal cord as well as in dorsal root ganglion (DRG) neurons after either non-noxious colorectal distension (CRD) or trinitrobenzenesulfonic acid (TNBS)-induced colitis in the adult rat. In both preparations, c- fos was expressed in similar spinal cord regions, including medial and lateral dorsal horn, dorsal commissure (DCM; laminae X above the central canal), and the sacral parasympathetic nucleus (SPN, laminae V–VII). However, TNBS-induced colitis produced significantly larger numbers (8–10-fold increase over control) of Fos-positive spinal cord neurons. In addition, there was also a significant increase (3–4-fold) in the number of Jun-positive colon DRG neurons after colitis compared with CRD. Nepadutant had no significant effect on proto-oncogene expression induced by CRD in either spinal cord neurons or DRG neurons. In contrast, nepadutant significantly decreased (70%) the number of Fos-positive neurons in dorsal horn, DCM, and SPN spinal cord regions and significantly decreased (75%) the number of Jun-positive DRG neurons after TNBS-induced irritation of the colon. These findings indicate that nepadutant suppresses the responses of colonic afferent neurons to nociceptive stimuli and that NK2 Receptor Antagonists may be beneficial in the treatment of sensory symptoms of colitis.
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the possible role of atp and pacap as mediators of apamin sensitive nanc inhibitory junction potentials in circular muscle of guinea pig colon
British Journal of Pharmacology, 1996Co-Authors: Vladimir P Zagorodnyuk, Carlo Alberto Maggi, Paolo Santicioli, Antonio GiachettiAbstract:Abstract 1. In the presence of atropine (1 microM), guanethidine (3 microM), indomethacin (3 microM), nifedipine (1 microM), L-nitroarginine (L-NOARG, 100 microM), and the selective tachykinin NK1 and NK2 Receptor Antagonists, SR 140,333 and GR 94,800, respectively (0.1 microM each), a single pulse of electrical field stimulation (EFS) produced a monophasic non-adrenergic non-cholinergic (NANC) inhibitory junction potential (i.j.p., about 10 mV in amplitude) in the circular muscle of guinea-pig proximal colon, recorded by the modified single sucrose gap technique. 2. The P2 purinoceptor agonist, alpha, beta methylene ATP (alpha, beta mATP, 100 microM) and the pituitary adenylyl cyclase activating peptide (PACAP, 1 microM) both produced hyperpolarization (11 +/- 0.8 mV, n = 14 and 10.2 +/- 0.8 mV, n = 19, respectively) and relaxation (1.1 +/- 0.2 mV, n = 14 and 1.5 +/- 0.2 mN, n = 19, respectively) of the circular muscle. 3. Apamin (0.1 microM) nearly abolished (about 90% inhibition) the NANC i.j.p. and the alpha, beta mATP-induced hyperpolarization, markedly reduced the alpha, beta mATP-induced relaxation (73% inhibition) and the PACAP-induced hyperpolarization (65% inhibition), while the PACAP-induced relaxation was unaffected. 4. Tetraethylammonium (TEA, 10 mM) increased the EFS-evoked i.j.p. and revealed an excitatory junction potential (e.j.p.). In the presence of TEA, alpha, beta mATP induced a biphasic response: transient depolarization and contraction followed by hyperpolarization and relaxation. The hyperpolarization to PACAP was reduced by TEA (45% inhibition) but the relaxation was unaffected. 5. The combined application of apamin (0.1 microM) and TEA (10 mM) abolished the i.j.p. and single pulse EFS evoked a pure e.j.p. with latency three times longer than that of the i.j.p. In the majority of strips tested, alpha, beta mATP and PACAP elicited a biphasic response : depolarization and small contraction followed by hyperpolarization and relaxation. 6. The P2 purinoceptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) inhibited the NANC i.j.p. in concentration-dependent manner and inhibited the alpha, beta mATP-induced hyperpolarization and relaxation, without affecting the hyperpolarization and relaxation induced by PACAP. On the other hand, the P2 purinoceptor antagonist, suramin (100 microM) inhibited to a similar extent (60-80%) the NANC i.j.p. and the hyperpolarization and relaxation induced by alpha, beta mATP or PACAP. 7. PPADS and suramin reduced the NANC e.j.p. evoked by a single pulse EFS in the presence of apamin and TEA (100 microM of PPADS and 300 microM of suramin inhibited the e.j.p. by about 40%). 8. We conclude that ATP, but not PACAP, mediates the apamin-sensitive NANC i.j.p. in the circular muscle of the guinea-pig colon. After blockade of the NANC i.j.p., ATP may act as an excitatory transmitter by activating excitatory P2 purinoceptors. The subtypes of P2 purinoceptor involved in the inhibitory and excitatory responses remain to be established. The data suggest that excitatory P2 purinoceptors may be located extrajunctionally.
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tachykinin nk1 and NK2 Receptor Antagonists and atropine resistant ascending excitatory reflex to the circular muscle of the guinea pig ileum
British Journal of Pharmacology, 1994Co-Authors: Carlo Alberto Maggi, Riccardo Patacchini, Lorand Bartho, Peter Holzer, Paolo SanticioliAbstract:Abstract 1. The aim of this study was to investigate the effect of various Antagonists, selective for the tachykinin NK1 or NK2 Receptor, on the atropine-resistant ascending excitatory reflex (AER) to the circular muscle of the guinea-pig ileum elicited by radial stretch (balloon distension) or electrical field stimulation. 2. Submaximal and maximal atropine- (1 microM) resistant AER elicited by balloon distension averaged about 40-50% and 70-90% of maximal circular spasm to 80 mM KCl, respectively. The NK1 Receptor antagonist, (+/)-CP 96,345 (1 microM) inhibited both maximal and submaximal AER. FK 888 (1-3 microM) inhibited submaximal AER only. RP 67,580 (1 microM) was ineffective. The NK2 Receptor antagonist, GR 94,800, inhibited both maximal and submaximal AER at all concentrations tested (0.1-3.0 microM), while SR 48,968 was effective only at 1.0 microM. The NK2 Receptor Antagonists, MEN 10,376 and MEN 10,573 inhibited both submaximal and maximal AER at 10 and 1.0 microM, respectively. 3. In other experiments, an NK1 Receptor antagonist, (+/-)-CP 96,345 or FK 888 (1.0 microM in each case) was administered first and the effect of GR 94,800 (1.0 microM) on the residual AER response was determined; or GR 94,800 was administered first and the effect of (+/-)-CP 96,345 or FK 888 was determined. The results of these experiments indicated an additive effect produced by the combined treatment with NK1 and NK2 Receptor Antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
C K Buckner - One of the best experts on this subject based on the ideXlab platform.
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4 alkylpiperidines related to sr 48968 potent Antagonists of the neurokinin 2 NK2 Receptor
Bioorganic & Medicinal Chemistry Letters, 1998Co-Authors: Robert T Jacobs, Ashok Shenvi, Russell C Mauger, Terrance G Ulatowski, D Aharony, C K BucknerAbstract:A series of 4-alkylpiperidine derivatives related to the potent neurokinin-2 (NK2) Receptor antagonist SR-48968 (1) is described. Simple aliphatic derivatives were found to be poorly active, but appropriate placement of an alcohol functional group afforded compounds that were of similar activity to 1. Several representatives in this series, such as the 4-(1-hydroxy-1-ethylpropyl)piperidine (14), were found to exhibit oral activity in a model of labored abdominal breathing in guinea pigs. These results expand the latitude of substituents available in this region of this series of NK2 Receptor Antagonists.
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differential blockade by tachykinin nk1 and NK2 Receptor Antagonists of bronchoconstriction induced by direct acting agonists and the indirect acting mimetics capsaicin serotonin and 2 methyl serotonin in the anesthetized guinea pig
Journal of Pharmacology and Experimental Therapeutics, 1993Co-Authors: C K Buckner, N Liberati, D Dea, D Lengel, C Stinsonfisher, J Campbell, S Miller, A Shenvi, R D KrellAbstract:This study has examined the abilities of (+/-)-CP96345 and (+/-)-SR48968, nonpeptide Antagonists selective for the tachykinin NK1 and NK2 Receptors, respectively, to block bronchoconstriction caused by intravenous administration of direct-acting Receptor agonists and the indirect-acting mimetics capsaicin, serotonin and 2-methyl-serotonin in the anesthetized guinea pig. The NK1 antagonist (+/-)-CP96345 was found to cause, at a maximally tolerated dose of 9 mumol/kg, an approximate 10-fold rightward shift of the dose-response curves for selective NK1 agonists substance P (SP), [Sar9,Met(O2)11]SP and Ac-[Arg6,Sar9,Met(O2)11]SP6-11 without altering responses to selective NK2 agonists neurokinin A (NKA), [Nle10]NKA4-10 or [beta-Ala8]NKA4-10. The NK2 antagonist (+/-)-SR48968 caused dose-dependent rightward shifts of the dose-response curves for the NK2 but not the NK1 agonists. Results using combinations of the Receptor Antagonists indicate that the NK2 agonists could cause bronchoconstriction by acting on the NK1 Receptors at large doses relative to those used without Antagonists. Of the agonists used here, [beta-Ala8]NKA4-10 appeared to be the most selective for the NK2 Receptors. When used alone, only (+/-)-SR48968 was found to block bronchoconstriction caused by capsaicin, serotonin (after blockade of 5-HT2 Receptors by LY53857) and 2-methyl-serotonin. When (+/-)-CP96345 was also given, larger additional blockade was seen with capsaicin than with serotonin or 2-methyl-serotonin as mimetic substance. Atropine caused small and variable degrees of blockade of serotonin and 2-methyl-serotonin but not of capsaicin after combinations of the two Antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
Alessandro Lecci - One of the best experts on this subject based on the ideXlab platform.
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discovery of a new series of potent and selective linear tachykinin NK2 Receptor Antagonists
Journal of Medicinal Chemistry, 2007Co-Authors: Valentina Fedi, Alessandro Lecci, Maria Altamura, Rosemarie Catalioto, Danilo Giannotti, Alessandro Giolitti, Sandro Giuliani, Antonio Guidi, Nicholas J S Harmat, Stefania MeiniAbstract:Starting from 1 (MEN14268), a selective tachykinin NK2 Receptor antagonist with an interesting in vitro pharmacological profile, a family of numerous Antagonists was obtained through an optimization process focused on iterated structural modifications. The effects of the introduction of a wide variety of substituents on the lipophilic aromatic part of the molecule and the modulation of the structural constraint through the insertion of different achiral alpha,alpha-dialkylamino acids were investigated. In particular, aromatic and benzofused heteroaromatic moieties were introduced at the pseudo-N-terminal residue to replace the 2-benzothiophene moiety, and a systematic investigation of the best positioning of substituents onto the aromatic platform was reported for the benzothiophene core. Studies on the modulation of the length and the rigidity of the hydrophilic pseudo-C-terminal pendant are presented. Many heteroaliphatic groups are well tolerated by the Receptor in this part of the ligand. The product 48f (MEN15596), bearing a methyl substituent on the benzothiophene and a tetrahydropyranylmethylpiperidine pendant, was finally selected for its good in vivo activity after intravenous, intraduodenal, and oral administration in guinea pigs.
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tachykinin NK2 Receptor Antagonists for the treatment of irritable bowel syndrome
British Journal of Pharmacology, 2004Co-Authors: Alessandro Lecci, Angela Capriati, Carlo Alberto MaggiAbstract:Tachykinin NK2 Receptors are expressed in the gastrointestinal tract of both laboratory animals and humans. Experimental data indicate a role for these Receptors in the regulation of intestinal motor functions (both excitatory and inhibitory), secretions, inflammation and visceral sensitivity. In particular, NK2 Receptor stimulation inhibits intestinal motility by activating sympathetic extrinsic pathways or NANC intramural inhibitory components, whereas a modulatory effect on cholinergic nerves or a direct effect on smooth muscle account for the NK2 Receptor-mediated increase in intestinal motility. Accordingly, selective NK2 Receptor Antagonists can reactivate inhibited motility or decrease inflammation- or stress-associated hypermotility. Intraluminal secretion of water is increased by NK2 Receptor agonists via a direct effect on epithelial cells, and this mechanism is active in models of diarrhoea since selective Antagonists reverse the increase in faecal water content in these models. Hyperalgesia in response to intraluminal volume signals is possibly mediated through the stimulation of NK2 Receptors located on peripheral branches of primary afferent neurones. NK2 Receptor Antagonists reduce the hyper-responsiveness that occurs following intestinal inflammation or application of stressful stimuli to animals. Likewise, NK2 Receptor Antagonists reduce intestinal tissue damage induced by chemical irritation of the intestinal wall or lumen. In healthy volunteers, the selective NK2 antagonist nepadutant reduced the motility-stimulating effects and irritable bowel syndrome-like symptoms triggered by intravenous infusion of neurokinin A, and displayed other characteristics that could support its use in patients. It is concluded that blockade of peripheral tachykinin NK2 Receptors should be considered as a viable mechanism for decreasing the painful symptoms and altered bowel habits of irritable bowel syndrome patients.
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effect of nepadutant a neurokinin 2 tachykinin Receptor antagonist on immediate early gene expression after trinitrobenzenesulfonic acid induced colitis in the rat
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Lori A Birder, Susanna Kiss, William C De Groat, Alessandro Lecci, Carlo Alberto MaggiAbstract:Tachykinins have been implicated in inflammatory responses such as those occurring in inflammatory bowel disease. Accordingly, we investigated the effect of a selective neurokinin (NK) 2 Receptor antagonist, nepadutant, on proto-oncogene expression in the L6-S1 spinal cord as well as in dorsal root ganglion (DRG) neurons after either non-noxious colorectal distension (CRD) or trinitrobenzenesulfonic acid (TNBS)-induced colitis in the adult rat. In both preparations, c- fos was expressed in similar spinal cord regions, including medial and lateral dorsal horn, dorsal commissure (DCM; laminae X above the central canal), and the sacral parasympathetic nucleus (SPN, laminae V–VII). However, TNBS-induced colitis produced significantly larger numbers (8–10-fold increase over control) of Fos-positive spinal cord neurons. In addition, there was also a significant increase (3–4-fold) in the number of Jun-positive colon DRG neurons after colitis compared with CRD. Nepadutant had no significant effect on proto-oncogene expression induced by CRD in either spinal cord neurons or DRG neurons. In contrast, nepadutant significantly decreased (70%) the number of Fos-positive neurons in dorsal horn, DCM, and SPN spinal cord regions and significantly decreased (75%) the number of Jun-positive DRG neurons after TNBS-induced irritation of the colon. These findings indicate that nepadutant suppresses the responses of colonic afferent neurons to nociceptive stimuli and that NK2 Receptor Antagonists may be beneficial in the treatment of sensory symptoms of colitis.
Selena Harrison - One of the best experts on this subject based on the ideXlab platform.
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capsaicin like effects of n arachidonoyl dopamine in the isolated guinea pig bronchi and urinary bladder
European Journal of Pharmacology, 2003Co-Authors: Selena Harrison, Luciano De Petrocellis, Marcello Trevisani, Francesca Benvenuti, Maurizio Bifulco, Pierangelo Geppetti, Vincenzo Di MarzoAbstract:A capsaicin-like endogenous ligand of vanilloid (VR1) Receptors, N-arachidonoyl-dopamine, was recently identified in bovine and rat nervous tissue, and found to be almost as potent as capsaicin, and 5–10-fold more potent than anandamide, on these Receptors, both in isolated cells and in vivo. Here we have investigated if N-arachidonoyl-dopamine also exerts other capsaicin-like effects at VR1 Receptors in some isolated organ preparations. N-arachidonoyl-dopamine exerted a potent contractile response of guinea pig isolated bronchi (EC50=12.6F1.7 AM, Emax=69.2F2.4% of carbachol Emax), which was blocked by pre-treatment with capsaicin or with the VR1 antagonist capsazepine, as well as by a combination of tachykinin NK1 and NK2 Receptor Antagonists. In this assay, N-arachidonoyldopamine was less and more potent and/or efficacious than capsaicin (EC50=40.0 nM; Emax=93.5%) and anandamide (EC50=15.2 AM, Emax=38.0%), respectively. Unlike capsaicin and anandamide, forskolin or ethanol did not enhance N-arachidonoyl-dopamine effect in this preparation, whereas epithelial denudation resulted in a 2.5-fold increase in potency without affecting the efficacy. N-arachidonoyl-dopamine also contracted the isolated guinea pig urinary bladder, although in this preparation, as well as in the isolated rat urinary bladder, the potency (EC50=3.7F0.3 and 19.9F0.1 AM) and/or efficacy (Emax=12.0F0.1% and 20.7F0.7% of carbachol Emax) of the compound were significantly lower than those of both capsaicin and anandamide. These data suggest that the extent to which exogenous N-arachidonoyldopamine activates VR1 Receptor in isolated organs is largely dependent on pharmacodynamics and bioavailability. D 2003 Elsevier B.V. All rights reserved.
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evidence that par 1 and par 2 mediate prostanoid dependent contraction in isolated guinea pig gallbladder
British Journal of Pharmacology, 2000Co-Authors: Michele Tognetto, Nigel W Bunnett, Marcello Trevisani, Pierangelo Geppetti, Barbara Maggiore, G Navarra, Alessandro Turini, Remo Guerrini, Selena HarrisonAbstract:We have investigated the ability of protease-activated Receptor-1 (PAR-1), PAR-2, PAR-3 and PAR-4 agonists to induce contractile responses in isolated guinea-pig gallbladder. Thrombin, trypsin, mouse PAR-1 activating (SFLLRN-NH2) peptide, and mouse PAR-2 activating (SLIGRL-NH2) and human PAR-2 activating (SLIGKV-NH2) peptides produced a concentration-dependent contractile response. Mouse PAR-4 activating (GYPGKF-NH2) peptide, the mouse PAR-1 reverse (NRLLFS-NH2) peptide, the mouse PAR-2 reverse (LRGILS-NH2) and human PAR-2 reverse (VKGILS-NH2) peptides caused negligible contractile responses at the highest concentrations tested. An additive effect was observed following the contractile response induced by either trypsin or thrombin, with the addition of a different PAR agonist (SFLLRN-NH2 and SLIGRL-NH2, respectively). Desensitization to PAR-2 activating peptide attenuated the response to trypsin but failed to attenuate the response to PAR-1 agonists, and conversely desensitization to PAR-1 attenuated the response to thrombin but failed to alter contractile responses to PAR-2 agonists. The contractile responses produced by thrombin, trypsin, SFLLRN-NH2 and SLIGRL-NH2 were markedly reduced in the presence of the cyclo-oxygenase inhibitor, indomethacin, whilst the small contractile response produced by NRLLFS-NH2 and LRGILS-NH2 were insensitive to indomethacin. The contractile responses to thrombin, trypsin, SFLLRN-NH2 and SLIGRL-NH2 were unaffected by the presence of: the non-selective muscarinic antagonist, atropine; the nitric oxide synthase inhibitor, L-NAME; the sodium channel blocker, tetrodotoxin; the combination of selective tachykinin NK1 and NK2 Receptor Antagonists, (S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl) piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2] octane chloride (SR140333) and (S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino-2-(3,4-dichlorophenyl)-butyl] benzamide (SR48968), respectively. The results indicate that PAR-1 and PAR-2 activation causes contractile responses in the guinea-pig gallbladder, an effect that is mediated principally by prostanoid release, and is independent of neural mechanisms. British Journal of Pharmacology (2000) 131, 689–694; doi:10.1038/sj.bjp.0703618
Vincenzo Di Marzo - One of the best experts on this subject based on the ideXlab platform.
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capsaicin like effects of n arachidonoyl dopamine in the isolated guinea pig bronchi and urinary bladder
European Journal of Pharmacology, 2003Co-Authors: Selena Harrison, Luciano De Petrocellis, Marcello Trevisani, Francesca Benvenuti, Maurizio Bifulco, Pierangelo Geppetti, Vincenzo Di MarzoAbstract:A capsaicin-like endogenous ligand of vanilloid (VR1) Receptors, N-arachidonoyl-dopamine, was recently identified in bovine and rat nervous tissue, and found to be almost as potent as capsaicin, and 5–10-fold more potent than anandamide, on these Receptors, both in isolated cells and in vivo. Here we have investigated if N-arachidonoyl-dopamine also exerts other capsaicin-like effects at VR1 Receptors in some isolated organ preparations. N-arachidonoyl-dopamine exerted a potent contractile response of guinea pig isolated bronchi (EC50=12.6F1.7 AM, Emax=69.2F2.4% of carbachol Emax), which was blocked by pre-treatment with capsaicin or with the VR1 antagonist capsazepine, as well as by a combination of tachykinin NK1 and NK2 Receptor Antagonists. In this assay, N-arachidonoyldopamine was less and more potent and/or efficacious than capsaicin (EC50=40.0 nM; Emax=93.5%) and anandamide (EC50=15.2 AM, Emax=38.0%), respectively. Unlike capsaicin and anandamide, forskolin or ethanol did not enhance N-arachidonoyl-dopamine effect in this preparation, whereas epithelial denudation resulted in a 2.5-fold increase in potency without affecting the efficacy. N-arachidonoyl-dopamine also contracted the isolated guinea pig urinary bladder, although in this preparation, as well as in the isolated rat urinary bladder, the potency (EC50=3.7F0.3 and 19.9F0.1 AM) and/or efficacy (Emax=12.0F0.1% and 20.7F0.7% of carbachol Emax) of the compound were significantly lower than those of both capsaicin and anandamide. These data suggest that the extent to which exogenous N-arachidonoyldopamine activates VR1 Receptor in isolated organs is largely dependent on pharmacodynamics and bioavailability. D 2003 Elsevier B.V. All rights reserved.