The Experts below are selected from a list of 288 Experts worldwide ranked by ideXlab platform
Carlo Alberto Maggi - One of the best experts on this subject based on the ideXlab platform.
-
Tachykinin Receptor assays.
Current protocols in pharmacology, 2010Co-Authors: Stefania Meini, Carlo Alberto MaggiAbstract:Described in this unit are methods for obtaining, preparing, and testing smooth muscle preparations bearing Tachykinin Receptors to study the agonist or antagonist properties of test compounds. Concentration-response curves to agonists are constructed to measure their ability to produce smooth muscle contractions and thus evaluate the potency and efficacy of the agonists. Antagonists are tested for their ability to shift the agonist concentration-response curve and to calculate their potency. Two different protocols are described for each of the three Tachykinin Receptors (NK(1), NK(2), and NK(3)). The NK(1) Receptor assays use guinea pig ileum longitudinal muscle myenteric plexus (GPI) and rat urinary bladder (RUB), the NK(2) Receptor assays use isolated endothelium-deprived rabbit pulmonary artery (RPA) and hamster trachea (HT), and the NK(3) Receptor assays use GPI and rat portal vein (RPV).
-
Current Protocols in Pharmacology - Tachykinin Receptor Assays
Current Protocols in Pharmacology, 2010Co-Authors: Stefania Meini, Carlo Alberto MaggiAbstract:Described in this unit are methods for obtaining, preparing, and testing smooth muscle preparations bearing Tachykinin Receptors to study the agonist or antagonist properties of test compounds. Concentration-response curves to agonists are constructed to measure their ability to produce smooth muscle contractions and thus evaluate the potency and efficacy of the agonists. Antagonists are tested for their ability to shift the agonist concentration-response curve and to calculate their potency. Two different protocols are described for each of the three Tachykinin Receptors (NK(1), NK(2), and NK(3)). The NK(1) Receptor assays use guinea pig ileum longitudinal muscle myenteric plexus (GPI) and rat urinary bladder (RUB), the NK(2) Receptor assays use isolated endothelium-deprived rabbit pulmonary artery (RPA) and hamster trachea (HT), and the NK(3) Receptor assays use GPI and rat portal vein (RPV).
-
Tachykinin Receptor antagonists in clinical trials
Expert Opinion on Investigational Drugs, 2009Co-Authors: Laura Quartara, Maria Altamura, Stefano Evangelista, Carlo Alberto MaggiAbstract:Tachykinins (TKs) are small peptides widely distributed in the central and peripheral nervous systems where they act as neurotransmitters. Potent and selective TKs antagonists have been developed in the last 20 years and many efforts have been made to prove their efficacy in the treatment of various diseases. Herein the most prominent results in the clinical development are reported and discussed. For aprepitant, the only compound of this class to have been launched to date, results of clinical studies and postmarketing cost-effectiveness data for the treatment of chemotherapy-induced emesis are discussed. The field is still well active, as currently proof-of-concept studies for indications initially missed (i.e., depression) are ongoing and new targets are under investigation.
-
UNIT 4.10 Tachykinin Receptor Assays
Current Protocols in Pharmacology, 1998Co-Authors: Riccardo Patacchini, Carlo Alberto MaggiAbstract:Described in this unit are methods for obtaining, preparing, and testing smooth muscle preparations bearing Tachykinin Receptors to study the agonist or antagonist properties of test compounds. Concentration-response curves to agonists are constructed to measure their ability to produce smooth muscle contractions and thus evaluate the potency and efficacy of the agonists. Antagonists are tested for their ability to shift the agonist concentration-response curve and to calculate their potency. Two different protocols are described for each of the three Tachykinin Receptors (NK1, NK2, and NK3). The NK1 Receptor assays use guinea pig ileum longitudinal muscle myenteric plexus (GPI) and rat urinary bladder (RUB), the NK2 Receptor assays use isolated endothelium-deprived rabbit pulmonary artery (RPA) and hamster trachea (HT), and the NK3 Receptor assays use GPI and rat portal vein (RPV). Curr. Protoc. Pharmacol. 48:4.10.1-4.10.28. © 2010 by John Wiley & Sons, Inc. Keywords: Tachykinin Receptor; smooth muscle; contractility; antagonism; agonism; in vitro bioassay; selectivity
-
Heterogeneity of NK-2 Tachykinin Receptors in hamster and rabbit smooth muscles.
Regulatory peptides, 1992Co-Authors: Carlo Alberto Maggi, Riccardo Patacchini, Laura Quartara, Anthony Eglezos, Antonio GiachettiAbstract:Abstract The possible existence of NK-2 Receptor subtypes in peripheral smooth muscle preparations from rabbit and hamster was investigated by studying the effect of neurokinin A, the selective NK-2 Receptor agonist [βAla 8 ] neurokinin A (4–10), the selective NK-2 Tachykinin Receptor antagonists, MEN 10,376, L 659,877 and R 396, and the pseudopeptide derivative of neurokinin A (4–10), MDL 28,564. All experiments were performed in the presence of peptidase inhibitors (captopril, bestatin and thiorphan, 1 μM each). Both neurokinin A and [βAla 8 ] neurokinin A (4–10) produced concentration-dependent contractions of the rabbit isolated bronchus and hamster isolated stomach and colon, as well as enhancement of the nerve-mediated twitches of rabbit isolated vas deferens (pars prostatica). MEN 10,376, L 659,877 and R 396 antagonized the effect of the NK-2 Receptor selective agonist in all four tissues under study, although marked differences in antagonist potency were evident for the three antagonists. Thus MEN 10,376 was distinctly more potent (about 100 times) in rabbit than in hamster preparations while L 659,877 and R 396 were more potent in hamster than rabbit preparations. MDL 28,564 showed a distinct agonist character in rabbit preparations while it was virtually inactive in hamster preparations, where it antagonized the effect of the NK-2 Receptor selective agonist. These findings provide further evidence for heterogeneity of the NK-2 Tachykinin Receptor which, on a pharmacological basis, can be classified in at least two subtypes as follows: NK-2A Receptors having the rank order of antagonist potency MEN 10,376 > L 659,877 > R 396 and NK-2B Receptors having the rank order of antagonist potency L 659,877 > R 396 > MEN 10,376 . MDL 28,564 has agonist activity at NK-2A Receptors and antagonist activity at NK-2B Receptors. It is as yet unclear as to whether NK-2A and NK-2B Receptors represent true Receptor subtypes or are species-related variations of the NK-2 Tachykinin Receptor.
Joseph P Yevich - One of the best experts on this subject based on the ideXlab platform.
-
patent update central peripheral nervous systems antimigraine agents july 1994 june 1995
Expert Opinion on Therapeutic Patents, 1995Co-Authors: Joseph P YevichAbstract:The patent literature pertaining to agents for the treatment of migraine headache and related disorders has been reviewed for the period of July 1, 1994 to June 30, 1995. Included are patents on serotonergic agents, i.e. 5-HT1D agonists, 5-HT2 Receptor ligands and 5-HT3 antagonists as well as patents disclosing chemical entities claimed to have potential antimigraine activity via non-serotonergic mechanisms, e.g. Tachykinin Receptor antagonists and nitric oxide synthetase inhibitors. Relevant references from the recent scientific literature have also been cited.
-
Patent Update: Central & Peripheral Nervous Systems: Antimigraine agents: July 1994 - June 1995
Expert Opinion on Therapeutic Patents, 1995Co-Authors: Joseph P YevichAbstract:The patent literature pertaining to agents for the treatment of migraine headache and related disorders has been reviewed for the period of July 1, 1994 to June 30, 1995. Included are patents on serotonergic agents, i.e. 5-HT1D agonists, 5-HT2 Receptor ligands and 5-HT3 antagonists as well as patents disclosing chemical entities claimed to have potential antimigraine activity via non-serotonergic mechanisms, e.g. Tachykinin Receptor antagonists and nitric oxide synthetase inhibitors. Relevant references from the recent scientific literature have also been cited.
C. A. Maggi - One of the best experts on this subject based on the ideXlab platform.
-
Peripheral Tachykinin Receptors as targets for new drugs.
European journal of pharmacology, 2001Co-Authors: R Patacchini, C. A. MaggiAbstract:Tachykinins are widely distributed in the peripheral nervous system of the respiratory, urinary and gastrointestinal tract, stored in enteric neurons and in peripheral nerve endings of capsaicin-sensitive primary afferent neurons from which are released by stimuli having both pathological and physiological relevance. The most studied effects produced by Tachykinins in these systems are smooth muscle contraction, plasma protein extravasation, mucus secretion and recruitment/activation of immune cells. The use of Tachykinin Receptor-selective antagonists and knockout animals has enabled to identify the involvement of Tachykinin NK(1), NK(2) and NK(3) Receptors as mediators of peripheral effects of Tachykinins in different systems/species. The bulk of data obtained in experimental animal models suggests that Tachykinins could contribute to the genesis of symptoms accompanying various human diseases including asthma/bronchial hyperreactivity, cystitis of various aetiology, inflammatory bowel diseases and irritable bowel syndrome. Tachykinin Receptor antagonists are expected to afford therapeutically relevant effects.
-
Peripheral actions of Tachykinins
Neuropeptides, 2000Co-Authors: Alessandro Lecci, F Carini, Sandro Giuliani, Manuela Tramontana, C. A. MaggiAbstract:Tachykinins mediate a variety of physiological processes in the gastrointestinal, pulmonary and genito-urinary tract mainly through the stimulation of NK1 and NK2 Receptors. Preclinical evidence obtained through the use of selective Tachykinin Receptor antagonists indicates that endogenous Tachykinins are involved in augmented smooth muscle contraction, vasodilatation, chemotaxis and activation of immune cells, mucus secretion, water absorption/secretion. Recent evidence also suggests that endogenous Tachykinins released at the peripheral level may play a role in visceral inflammation, hyperreflexia and hyperalgesia. Possible mechanisms underlying the stimulation of primary afferent neurons by Tachykinins may involve a direct excitation of these neurons and the release of mediators which sensitise or stimulate sensory nerves. Tachykinin Receptor antagonists could have a clinical utility in several human diseases such as irritable bowel syndrome, asthma, and in micturition disturbances characterized by a hyperactive bladder.
-
Affinity of R 396, an NK-2 Tachykinin Receptor antagonist, for NK-2 Receptors in preparations from different species.
Neuropeptides, 1992Co-Authors: C. A. Maggi, Riccardo Patacchini, Paolo Rovero, Antonio Giachetti, M. Astolfi, P.l.m. Van GiersbergenAbstract:We have assessed the affinity of R 396 (Ac. Leu-Asp-Gln-Trp-Phe-Gly NH2) in a number of NK-2 Tachykinin Receptor bearing-tissues from several species. The cyclic analog of R 396, (MEN 10354) was less potent and selective than the linear hexapeptide at NK-2 Tachykinin Receptors subtypes in the rabbit pulmonary artery and hamster trachea. The affinity of R 396, as measured by a smooth muscle contraction assay and a radioligand binding assay, was higher (about 10 fold) for NK-2 Receptors expressed in hamster tissues (urinary bladder, stomach and trachea) than in rat tissues (urinary bladder, vas deferens, colon and stomach) and a further drop in affinity was observed in bovine tissues (urinary bladder and stomach) or rabbit bronchus. The results are discussed in relation to the proposed existence of NK-2 Receptor subtypes and raise the question of the existence of species-related differences as compared to the existence of true Receptor subtypes.
Francisco M. Pinto - One of the best experts on this subject based on the ideXlab platform.
-
Autocrine regulation of human sperm motility by Tachykinins.
Reproductive biology and endocrinology : RB&E, 2010Co-Authors: Francisco M. Pinto, Cristina G Ravina, Manuel Fernández-sánchez, Nerea Subirán, Antonio Cejudo-román, Jon Irazusta, Nicolas Garrido, Luz CandenasAbstract:Background: We examined the presence and function of Tachykinins and the Tachykinin-degrading enzymes neprilysin (NEP) and neprilysin-2 (NEP2) in human spermatozoa. Methods: Freshly ejaculated semen was collected from forty-eight normozoospermic human donors. We analyzed the expression of substance P, neurokinin A, neurokinin B, hemokinin-1, NEP and NEP2 in sperm cells by reversetranscriptase polymerase chain reaction (RT-PCR), western blot and immunocytochemistry assays and evaluated the effects of the neprilysin and neprilysin-2 inhibitor phosphoramidon on sperm motility in the absence and presence of Tachykinin Receptor-selective antagonists. Sperm motility was measured using WHO procedures or computerassisted sperm analysis (CASA). Results: The mRNAs of the genes that encode substance P/neurokinin A (TAC1), neurokinin B (TAC3), hemokinin-1 (TAC4), neprilysin (MME) and neprilysin-2 (MMEL1) were expressed in human sperm. Immunocytochemistry studies revealed that Tachykinin and neprilysin proteins were present in spermatozoa and show specific and differential distributions. Phosphoramidon increased sperm progressive motility and its effects were reduced in the presence of the Tachykinin Receptor antagonists SR140333 (NK1 Receptor-selective) and SR48968 (NK2 Receptor-selective) but unmodified in the presence of SR142801 (NK3 Receptor-selective). Conclusion: These data show that Tachykinins are present in human spermatozoa and participate in the regulation of sperm motility. Tachykinin activity is regulated, at least in part, by neprilysins.
-
Ovarian steroids regulate Tachykinin and Tachykinin Receptor gene expression in the mouse uterus
Reproductive biology and endocrinology : RB&E, 2009Co-Authors: Francisco M. Pinto, Jocelyn N Pennefather, Eva N Patak, C. Oscar Pintado, Luz CandenasAbstract:Background: In the mouse uterus, pregnancy is accompanied by changes in Tachykinin and Tachykinin Receptor gene expression and in the uterotonic effects of endogenous Tachykinins. In this study we have investigated whether changes in Tachykinin expression and responses are a result of changes in ovarian steroid levels. Methods: We quantified the mRNAs of Tachykinins and Tachykinin Receptors in uteri from ovariectomized mice and studied their regulation in response to estrogen and progesterone using real-time quantitative RT-PCR. Early (3 h) and late (24 h) responses to estrogen were evaluated and the participation of the estrogen Receptors (ER), ERalpha and ERbeta, was analyzed by treating mice with propylpyrazole triol, a selective ERalpha agonist, or diarylpropionitrile, a selective agonist of ERbeta. Results: All genes encoding Tachykinins (Tac1, Tac2 and Tac4) and Tachykinin Receptors (Tacr1, Tacr2 and Tacr3) were expressed in uteri from ovariectomized mice. Estrogen increased Tac1 and Tacr1 mRNA after 3 h and decreased Tac1 and Tac4 expression after 24 h. Tac2 and Tacr3 mRNA levels were decreased by estrogen at both 3 and 24 h. Most effects of estrogen were also observed in animals treated with propylpyrazole triol. Progesterone treatment increased the levels of Tac2. Conclusion: These results show that the expression of Tachykinins and their Receptors in the mouse uterus is tightly and differentially regulated by ovarian steroids. Estrogen effects are mainly mediated by ERalpha supporting an essential role for this estrogen Receptor in the regulation of the tachykinergic system in the mouse uterus.
-
A role for Tachykinins in the regulation of human sperm motility
Human reproduction (Oxford England), 2007Co-Authors: Cristina G Ravina, Francisco M. Pinto, M. Seda, A. Orea, Manuel Fernández-sánchez, C.o. Pintado, M. Luz CandenasAbstract:BACKGROUND: Tachykinins and Tachykinin Receptors are widely distributed in the male reproductive tract and appear to be involved in reproduction. However, the function and expression of Tachykinins and their Receptors in human spermatozoa remain poorly studied. We analysed the effects of Tachykinins on sperm motility and characterized the population of Tachykinin Receptors in human spermatozoa. METHODS AND RESULTS: Motility analysis was performed following World Health Organization guidelines and we found that substance P (SP), human hemokinin-1 (hHK-1), neurokinin A (NKA) and neurokinin B (NKB) produced concentration-dependent increases in sperm progressive motility. The effects of Tachykinins were antagonized by the NK 1 Receptor-selective antagonist SR 140333, the NK 2 Receptor-selective antagonist, SR 48968 and, to a lesser extent, also by the NK 3 Receptor-selective antagonist SR 142801. Immunocytochemistry studies showed expression of the NK 1 , NK 2 and NK 3 Tachykinin Receptor proteins in spermatozoa with different major sites of localization for each Receptor. Western blot analysis confirmed the presence of Tachykinin Receptors in sperm cell homogenates. RT-PCR demonstrated expression of the genes that encode SP/NKA (TACT), NKB (TAC3) and hHK-1 (TAC4) but not the genes TACR1, TACR2 and TACR3 encoding NK 1 , NK 2 and NK 3 Receptors, respectively. CONCLUSIONS: These results show for the first time that the NK 1 , NK 2 and NK 3 Tachykinin Receptor proteins are present in human spermatozoa. Our findings suggest that Tachykinins, probably acting through these three Tachykinin Receptors, play a role in the regulation of human sperm motility.
-
Tachykinins and Tachykinin Receptors: Structure and Activity Relationships
Current medicinal chemistry, 2004Co-Authors: Teresa A. Almeida, Francisco M. Pinto, Javier Rojo, Pedro M. Nieto, Mariano Hernández, J. D. Martin, M. Luz CandenasAbstract:In addition to the classical neurotransmitters, acetylcholine and noradrenaline, a wide number of peptides with neurotransmitter activity have been identified in the past few years. Among them, the Tachykinins substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) appear to act as mediators of nonadrenergic, noncholinergic (NANC) excitatory neurotransmission. Tachykinins interact with specific membrane proteins, belonging to the family of G protein-coupling cell membrane Receptors. Until now, three Tachykinin Receptors termed NK1 (NK1R), NK2 (NK2R) and NK3 (NK3R) have been cloned in different species. A large amount of reports suggests that these peptides are involved in nociception and neuroimmunomodulation, and in the development of different diseases such as bronchial asthma, inflammatory bowel syndrome and psychiatric disorders. Tachykinin Receptor antagonists are therefore promising, therapeutically relevant agents. However, and in spite of extensive research, the obtention of selective antagonists of Tachykinin Receptors have revealed very difficult. An understanding of how ligands interact with their Receptors is essential to permit a rational design of compounds acting selectively at the Tachykinin Receptor level. The major aim of the present article is to review the structure-activity data that exist for Tachykinins and their Receptors, with the purpose of getting insight into basic structural requirements that determine ligand / Receptor interaction.
Luz Candenas - One of the best experts on this subject based on the ideXlab platform.
-
Autocrine regulation of human sperm motility by Tachykinins.
Reproductive biology and endocrinology : RB&E, 2010Co-Authors: Francisco M. Pinto, Cristina G Ravina, Manuel Fernández-sánchez, Nerea Subirán, Antonio Cejudo-román, Jon Irazusta, Nicolas Garrido, Luz CandenasAbstract:Background: We examined the presence and function of Tachykinins and the Tachykinin-degrading enzymes neprilysin (NEP) and neprilysin-2 (NEP2) in human spermatozoa. Methods: Freshly ejaculated semen was collected from forty-eight normozoospermic human donors. We analyzed the expression of substance P, neurokinin A, neurokinin B, hemokinin-1, NEP and NEP2 in sperm cells by reversetranscriptase polymerase chain reaction (RT-PCR), western blot and immunocytochemistry assays and evaluated the effects of the neprilysin and neprilysin-2 inhibitor phosphoramidon on sperm motility in the absence and presence of Tachykinin Receptor-selective antagonists. Sperm motility was measured using WHO procedures or computerassisted sperm analysis (CASA). Results: The mRNAs of the genes that encode substance P/neurokinin A (TAC1), neurokinin B (TAC3), hemokinin-1 (TAC4), neprilysin (MME) and neprilysin-2 (MMEL1) were expressed in human sperm. Immunocytochemistry studies revealed that Tachykinin and neprilysin proteins were present in spermatozoa and show specific and differential distributions. Phosphoramidon increased sperm progressive motility and its effects were reduced in the presence of the Tachykinin Receptor antagonists SR140333 (NK1 Receptor-selective) and SR48968 (NK2 Receptor-selective) but unmodified in the presence of SR142801 (NK3 Receptor-selective). Conclusion: These data show that Tachykinins are present in human spermatozoa and participate in the regulation of sperm motility. Tachykinin activity is regulated, at least in part, by neprilysins.
-
Ovarian steroids regulate Tachykinin and Tachykinin Receptor gene expression in the mouse uterus
Reproductive biology and endocrinology : RB&E, 2009Co-Authors: Francisco M. Pinto, Jocelyn N Pennefather, Eva N Patak, C. Oscar Pintado, Luz CandenasAbstract:Background: In the mouse uterus, pregnancy is accompanied by changes in Tachykinin and Tachykinin Receptor gene expression and in the uterotonic effects of endogenous Tachykinins. In this study we have investigated whether changes in Tachykinin expression and responses are a result of changes in ovarian steroid levels. Methods: We quantified the mRNAs of Tachykinins and Tachykinin Receptors in uteri from ovariectomized mice and studied their regulation in response to estrogen and progesterone using real-time quantitative RT-PCR. Early (3 h) and late (24 h) responses to estrogen were evaluated and the participation of the estrogen Receptors (ER), ERalpha and ERbeta, was analyzed by treating mice with propylpyrazole triol, a selective ERalpha agonist, or diarylpropionitrile, a selective agonist of ERbeta. Results: All genes encoding Tachykinins (Tac1, Tac2 and Tac4) and Tachykinin Receptors (Tacr1, Tacr2 and Tacr3) were expressed in uteri from ovariectomized mice. Estrogen increased Tac1 and Tacr1 mRNA after 3 h and decreased Tac1 and Tac4 expression after 24 h. Tac2 and Tacr3 mRNA levels were decreased by estrogen at both 3 and 24 h. Most effects of estrogen were also observed in animals treated with propylpyrazole triol. Progesterone treatment increased the levels of Tac2. Conclusion: These results show that the expression of Tachykinins and their Receptors in the mouse uterus is tightly and differentially regulated by ovarian steroids. Estrogen effects are mainly mediated by ERalpha supporting an essential role for this estrogen Receptor in the regulation of the tachykinergic system in the mouse uterus.
