The Experts below are selected from a list of 2004 Experts worldwide ranked by ideXlab platform
Thomas J. Gardella - One of the best experts on this subject based on the ideXlab platform.
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Inverse Agonism and the pth pthrp receptor
International Congress Series, 2003Co-Authors: Robert C. Gensure, Percy H. Carter, Thomas J. GardellaAbstract:Abstract The PTH/PTHrP receptor (PPR) is a family B G protein-coupled receptor that plays a vital role in calcium homeostasis and skeletal development. We are using photoaffinity cross-linking methods to explore how Inverse agonists interact with constitutively active mutant PPRs. The analog [para-benzoyl-phenylalanine (Bpa)2]PTHrP(1–36) is a selective Inverse agonist for PPR-H223R (altered in transmembrane domain (TMD) 2), while [ d -Bpa12]PTHrP(5–36) is an Inverse agonist for both PPR-H223R and PPR-T410P (altered in TMD 6). In each ligand, the photolabile Bpa group is the key determinant of Inverse Agonism. The [Bpa2]PTHrP(1–36) analog cross-linked to two sites in PPR-H223R: a primary site near the extracellular end of TMD 6 and a secondary site within TMD 4, extracellular loop 2 or TMD 5. Mutational studies revealed that the intensity of cross-linking to TMD 6, relative to TMD 4/5, increased as receptor signaling activity increased. Our preliminary mapping studies with [ d -Bpa12]PTHrP(5–36) indicate that this analog cross-links to a different site, possibly near the boundary of TMD 1 and the N-terminal domain. Thus, there appear to be two different mechanisms by which Inverse Agonism can be achieved in constitutively active PPRs. The studies also reveal conformational differences between active and inactive state PPRs, at least in the vicinity of residue 2 of the ligand.
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Inverse Agonism and the PTH/PTHrP receptor
International Congress Series, 2003Co-Authors: Robert C. Gensure, Percy H. Carter, Thomas J. GardellaAbstract:Abstract The PTH/PTHrP receptor (PPR) is a family B G protein-coupled receptor that plays a vital role in calcium homeostasis and skeletal development. We are using photoaffinity cross-linking methods to explore how Inverse agonists interact with constitutively active mutant PPRs. The analog [para-benzoyl-phenylalanine (Bpa)2]PTHrP(1–36) is a selective Inverse agonist for PPR-H223R (altered in transmembrane domain (TMD) 2), while [ d -Bpa12]PTHrP(5–36) is an Inverse agonist for both PPR-H223R and PPR-T410P (altered in TMD 6). In each ligand, the photolabile Bpa group is the key determinant of Inverse Agonism. The [Bpa2]PTHrP(1–36) analog cross-linked to two sites in PPR-H223R: a primary site near the extracellular end of TMD 6 and a secondary site within TMD 4, extracellular loop 2 or TMD 5. Mutational studies revealed that the intensity of cross-linking to TMD 6, relative to TMD 4/5, increased as receptor signaling activity increased. Our preliminary mapping studies with [ d -Bpa12]PTHrP(5–36) indicate that this analog cross-links to a different site, possibly near the boundary of TMD 1 and the N-terminal domain. Thus, there appear to be two different mechanisms by which Inverse Agonism can be achieved in constitutively active PPRs. The studies also reveal conformational differences between active and inactive state PPRs, at least in the vicinity of residue 2 of the ligand.
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identification of determinants of Inverse Agonism in a constitutively active parathyroid hormone parathyroid hormone related peptide receptor by photoaffinity cross linking and mutational analysis
Journal of Biological Chemistry, 2001Co-Authors: Robert C. Gensure, Percy H. Carter, Brian D. Petroni, Harald Jüppner, Thomas J. GardellaAbstract:We have investigated receptor structural components responsible for ligand-dependent Inverse Agonism in a constitutively active mutant of the human parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor type 1 (hP1R). This mutant receptor, hP1R-H223R (hP1R(CAM-HR)), was originally identified in Jansen's chondrodysplasia and is altered in transmembrane domain (TM) 2. We utilized the PTHrP analog, [Bpa(2),Ile(5),Trp(23),Tyr(36)]PTHrP-(1-36)-amide (Bpa(2)-PTHrP-(1-36)), which has valine 2 replaced by p-benzoyl-l-phenylalanine (Bpa); this substitution renders the peptide a photoreactive Inverse agonist at hP1R(CAM-HR). This analog cross-linked to hP1R(CAM-HR) at two contiguous receptor regions as follows: the principal cross-link site (site A) was between receptor residues Pro(415)-Met(441), spanning the TM6/extracellular loop three boundary; the second cross-link site (site B) was within the TM4/TM5 region. Within the site A interval, substitution of Met(425) to Leu converted Bpa(2)-PTHrP-(1-36) from an Inverse agonist to a weak partial agonist; this conversion was accompanied by a relative shift of cross-linking from site A to site B. The functional effect of the M425L mutation was specific for Bpa(2)-containing analogs, as Inverse Agonism of Bpa(2)-PTH-(1-34) was similarly eliminated, whereas Inverse Agonism of [Leu(11),d-Trp(12)]PTHrP-(5-36) was not affected. Overall, our data indicate that interactions between residue 2 of the ligand and the extracellular end of TM6 of the hP1R play an important role in modulating the conversion between active and inactive receptor states.
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Identification of determinants of Inverse Agonism in a constitutively active parathyroid hormone/parathyroid hormone-related peptide receptor by photoaffinity cross-linking and mutational analysis.
The Journal of biological chemistry, 2001Co-Authors: Robert C. Gensure, Percy H. Carter, Brian D. Petroni, Harald Jüppner, Thomas J. GardellaAbstract:We have investigated receptor structural components responsible for ligand-dependent Inverse Agonism in a constitutively active mutant of the human parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor type 1 (hP1R). This mutant receptor, hP1R-H223R (hP1R(CAM-HR)), was originally identified in Jansen's chondrodysplasia and is altered in transmembrane domain (TM) 2. We utilized the PTHrP analog, [Bpa(2),Ile(5),Trp(23),Tyr(36)]PTHrP-(1-36)-amide (Bpa(2)-PTHrP-(1-36)), which has valine 2 replaced by p-benzoyl-l-phenylalanine (Bpa); this substitution renders the peptide a photoreactive Inverse agonist at hP1R(CAM-HR). This analog cross-linked to hP1R(CAM-HR) at two contiguous receptor regions as follows: the principal cross-link site (site A) was between receptor residues Pro(415)-Met(441), spanning the TM6/extracellular loop three boundary; the second cross-link site (site B) was within the TM4/TM5 region. Within the site A interval, substitution of Met(425) to Leu converted Bpa(2)-PTHrP-(1-36) from an Inverse agonist to a weak partial agonist; this conversion was accompanied by a relative shift of cross-linking from site A to site B. The functional effect of the M425L mutation was specific for Bpa(2)-containing analogs, as Inverse Agonism of Bpa(2)-PTH-(1-34) was similarly eliminated, whereas Inverse Agonism of [Leu(11),d-Trp(12)]PTHrP-(5-36) was not affected. Overall, our data indicate that interactions between residue 2 of the ligand and the extracellular end of TM6 of the hP1R play an important role in modulating the conversion between active and inactive receptor states.
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Inverse Agonism of amino-terminally truncated parathyroid hormone (PTH) and PTH-related peptide (PTHrP) analogs revealed with constitutively active mutant PTH/PTHrP receptors.
Endocrinology, 1996Co-Authors: Thomas J. Gardella, Michael D. Luck, Geoffrey S. Jensen, Ernestina Schipani, John T. Potts, Harald JüppnerAbstract:Inverse agonists, ligands that suppress spontaneous receptor signaling activity, have been described for a growing number of G protein-coupled receptors; however, none have been reported for the PTH/calcitonin/secretin receptor family. We took advantage of the constitutive signaling activity of two mutant forms of the PTH/PTH-related peptide (PTHrP) receptor, recently identified in patients with Jansen's metaphyseal chondrodysplasia, to screen for PTH and PTHrP analogs with Inverse agonist activity. Two antagonist peptides, [Leu11, D-Trp12]hPTHrP(7-34)NH2 and [D-Trp12, Tyr34]bPTH-(7-34)NH2, displayed Inverse agonist activity and reduced cAMP in COS-7 cells expressing either mutant receptor by 30-50% (EC50 approximately 50 nM). These data demonstrate that the concept of Inverse Agonism can be extended to this distinct family of G protein-coupled receptors and their cognate antagonist peptide ligands. Such ligands shall be useful probes of the multi-state conformational equilibria proposed for these recepto...
Harald Jüppner - One of the best experts on this subject based on the ideXlab platform.
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identification of determinants of Inverse Agonism in a constitutively active parathyroid hormone parathyroid hormone related peptide receptor by photoaffinity cross linking and mutational analysis
Journal of Biological Chemistry, 2001Co-Authors: Robert C. Gensure, Percy H. Carter, Brian D. Petroni, Harald Jüppner, Thomas J. GardellaAbstract:We have investigated receptor structural components responsible for ligand-dependent Inverse Agonism in a constitutively active mutant of the human parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor type 1 (hP1R). This mutant receptor, hP1R-H223R (hP1R(CAM-HR)), was originally identified in Jansen's chondrodysplasia and is altered in transmembrane domain (TM) 2. We utilized the PTHrP analog, [Bpa(2),Ile(5),Trp(23),Tyr(36)]PTHrP-(1-36)-amide (Bpa(2)-PTHrP-(1-36)), which has valine 2 replaced by p-benzoyl-l-phenylalanine (Bpa); this substitution renders the peptide a photoreactive Inverse agonist at hP1R(CAM-HR). This analog cross-linked to hP1R(CAM-HR) at two contiguous receptor regions as follows: the principal cross-link site (site A) was between receptor residues Pro(415)-Met(441), spanning the TM6/extracellular loop three boundary; the second cross-link site (site B) was within the TM4/TM5 region. Within the site A interval, substitution of Met(425) to Leu converted Bpa(2)-PTHrP-(1-36) from an Inverse agonist to a weak partial agonist; this conversion was accompanied by a relative shift of cross-linking from site A to site B. The functional effect of the M425L mutation was specific for Bpa(2)-containing analogs, as Inverse Agonism of Bpa(2)-PTH-(1-34) was similarly eliminated, whereas Inverse Agonism of [Leu(11),d-Trp(12)]PTHrP-(5-36) was not affected. Overall, our data indicate that interactions between residue 2 of the ligand and the extracellular end of TM6 of the hP1R play an important role in modulating the conversion between active and inactive receptor states.
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Identification of determinants of Inverse Agonism in a constitutively active parathyroid hormone/parathyroid hormone-related peptide receptor by photoaffinity cross-linking and mutational analysis.
The Journal of biological chemistry, 2001Co-Authors: Robert C. Gensure, Percy H. Carter, Brian D. Petroni, Harald Jüppner, Thomas J. GardellaAbstract:We have investigated receptor structural components responsible for ligand-dependent Inverse Agonism in a constitutively active mutant of the human parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor type 1 (hP1R). This mutant receptor, hP1R-H223R (hP1R(CAM-HR)), was originally identified in Jansen's chondrodysplasia and is altered in transmembrane domain (TM) 2. We utilized the PTHrP analog, [Bpa(2),Ile(5),Trp(23),Tyr(36)]PTHrP-(1-36)-amide (Bpa(2)-PTHrP-(1-36)), which has valine 2 replaced by p-benzoyl-l-phenylalanine (Bpa); this substitution renders the peptide a photoreactive Inverse agonist at hP1R(CAM-HR). This analog cross-linked to hP1R(CAM-HR) at two contiguous receptor regions as follows: the principal cross-link site (site A) was between receptor residues Pro(415)-Met(441), spanning the TM6/extracellular loop three boundary; the second cross-link site (site B) was within the TM4/TM5 region. Within the site A interval, substitution of Met(425) to Leu converted Bpa(2)-PTHrP-(1-36) from an Inverse agonist to a weak partial agonist; this conversion was accompanied by a relative shift of cross-linking from site A to site B. The functional effect of the M425L mutation was specific for Bpa(2)-containing analogs, as Inverse Agonism of Bpa(2)-PTH-(1-34) was similarly eliminated, whereas Inverse Agonism of [Leu(11),d-Trp(12)]PTHrP-(5-36) was not affected. Overall, our data indicate that interactions between residue 2 of the ligand and the extracellular end of TM6 of the hP1R play an important role in modulating the conversion between active and inactive receptor states.
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Inverse Agonism of amino-terminally truncated parathyroid hormone (PTH) and PTH-related peptide (PTHrP) analogs revealed with constitutively active mutant PTH/PTHrP receptors.
Endocrinology, 1996Co-Authors: Thomas J. Gardella, Michael D. Luck, Geoffrey S. Jensen, Ernestina Schipani, John T. Potts, Harald JüppnerAbstract:Inverse agonists, ligands that suppress spontaneous receptor signaling activity, have been described for a growing number of G protein-coupled receptors; however, none have been reported for the PTH/calcitonin/secretin receptor family. We took advantage of the constitutive signaling activity of two mutant forms of the PTH/PTH-related peptide (PTHrP) receptor, recently identified in patients with Jansen's metaphyseal chondrodysplasia, to screen for PTH and PTHrP analogs with Inverse agonist activity. Two antagonist peptides, [Leu11, D-Trp12]hPTHrP(7-34)NH2 and [D-Trp12, Tyr34]bPTH-(7-34)NH2, displayed Inverse agonist activity and reduced cAMP in COS-7 cells expressing either mutant receptor by 30-50% (EC50 approximately 50 nM). These data demonstrate that the concept of Inverse Agonism can be extended to this distinct family of G protein-coupled receptors and their cognate antagonist peptide ligands. Such ligands shall be useful probes of the multi-state conformational equilibria proposed for these recepto...
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Inverse Agonism of amino terminally truncated parathyroid hormone pth and pth related peptide pthrp analogs revealed with constitutively active mutant pth pthrp receptors
Endocrinology, 1996Co-Authors: Thomas J. Gardella, Michael D. Luck, Geoffrey S. Jensen, Ernestina Schipani, John T. Potts, Harald JüppnerAbstract:Inverse agonists, ligands that suppress spontaneous receptor signaling activity, have been described for a growing number of G protein-coupled receptors; however, none have been reported for the PTH/calcitonin/secretin receptor family. We took advantage of the constitutive signaling activity of two mutant forms of the PTH/PTH-related peptide (PTHrP) receptor, recently identified in patients with Jansen's metaphyseal chondrodysplasia, to screen for PTH and PTHrP analogs with Inverse agonist activity. Two antagonist peptides, [Leu11, D-Trp12]hPTHrP(7-34)NH2 and [D-Trp12, Tyr34]bPTH-(7-34)NH2, displayed Inverse agonist activity and reduced cAMP in COS-7 cells expressing either mutant receptor by 30-50% (EC50 approximately 50 nM). These data demonstrate that the concept of Inverse Agonism can be extended to this distinct family of G protein-coupled receptors and their cognate antagonist peptide ligands. Such ligands shall be useful probes of the multi-state conformational equilibria proposed for these receptors and could lead to new approaches for treating human diseases caused by receptor activating mutations.
John A Harvey - One of the best experts on this subject based on the ideXlab platform.
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Inverse Agonism at serotonin and cannabinoid receptors.
Progress in molecular biology and translational science, 2010Co-Authors: Vincent J. Aloyo, William P. Clarke, Kelly A. Berg, Umberto Spampinato, John A HarveyAbstract:Abstract Contemporary receptor theory was developed to account for the existence of constitutive activity, as defined by the presence of receptor signaling in the absence of any ligand. In vitro studies with a variety of cell types have revealed the existence of constitutive activity and Inverse Agonism at a large number of receptors and also additional complexities of ligand–receptor interactions. Thus, ligands acting at a constitutively active receptor can act as agonists, antagonists, and/or Inverse agonists, and these pharmacological characteristics can differ for an individual ligand depending upon the receptor response measured and the physiological state of the system under study. Studies with a variety of cell types have established that the serotonin 5-HT2A and 5-HT2C receptors and the cannabinoid CB1 receptor demonstrate constitutive activity and Inverse Agonism in vitro. Serotonin and cannabinoid receptors are involved in a large number of physiological and behavioral functions. The possible existence of constitutive activity and Inverse Agonism at these receptors in vivo would provide new avenues for drug development. Recent studies have provided compelling evidence that both the serotonin 5-HT2A and 5-HT2C receptors and cannabinoid CB1 receptor demonstrate Inverse Agonism and constitutive activity also in vivo. This chapter describes our current knowledge of constitutive activity in vitro and then examines the evidence for constitutive activity in vivo.
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Current status of Inverse Agonism at serotonin2A (5-HT2A) and 5-HT2C receptors.
Pharmacology & therapeutics, 2008Co-Authors: Vincent J. Aloyo, William P. Clarke, Kelly A. Berg, Umberto Spampinato, John A HarveyAbstract:Contemporary receptor theory was developed to account for the existence of constitutive activity, as defined by the presence of receptor signaling in the absence of any ligand. Thus, ligands acting at a constitutively active receptor, can act as agonists, antagonists, and Inverse agonists. In vitro studies have also revealed the complexity of ligand/receptor interactions including agonist-directed stimulus trafficking, a finding that has led to multi-active state models of receptor function. Studies with a variety of cell types have established that the serotonin 5-HT(2A) and 5-HT(2C) receptors also demonstrate constitutive activity and Inverse Agonism. However, until recently, there has been no evidence to suggest that these receptors also demonstrate constitutive activity and hence reveal Inverse agonist properties of ligands in vivo. This paper describes our current knowledge of constitutive activity in vitro and then examines the evidence for constitutive activity in vivo. Both the serotonin 5-HT(2A) and 5-HT(2C) receptors are involved in a number of physiological and behavioral functions and are the targets for treatment of schizophrenia, anxiety, weight control, Parkinsonism, and other disorders. The existence of constitutive activity at these receptors in vivo, along with the possibility of Inverse Agonism, provides new avenues for drug development.
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Effect of 5-HT2 receptor antagonists on a cranial nerve reflex in the rabbit: evidence for Inverse Agonism
Psychopharmacology, 1999Co-Authors: John A Harvey, S. E. Welsh, H. Hood, Anthony G. RomanoAbstract:This study examined the role of the serotonin 5-HT2 receptor in motor function by examining the effect of antagonists on the motor performance of a cranial nerve reflex, the nictitating membrane (NM) reflex of the rabbit. The NM reflex was elicited by varying intensities of a tactile stimulus and the magnitudes of the elicited responses were measured at each intensity. Dose-response curves were obtained for the effects of several 5-HT2 receptor antagonists on response magnitude. d-Bromolysergic acid diethylamide (BOL), LY-53,857 and ketanserin had no significant effect on the magnitude of the NM reflex, indicating that they are neutral antagonists. However, the 5-HT2 receptor antagonists ritanserin, MDL-11,939 and mianserin produced a significant reduction in response magnitude with no significant effects on response frequency, suggesting that they were acting as Inverse agonists at the 5-HT2 receptor. The reduction in reflex magnitude produced by mianserin (10 µmol/kg) was fully blocked by BOL (5.8 µmol/kg), supporting the conclusion that mianserin was producing a reduction in reflex magnitude through an effect at the 5-HT2 receptor. The occurrence of Inverse Agonism suggests the possible existence of constitutive activity in vivo. We conclude that the 5-HT2 receptor (either 2A or 2C) plays an important role in motor function, perhaps by providing a tonic influence on motor systems.
J.- Arrang - One of the best experts on this subject based on the ideXlab platform.
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effects of betahistine at histamine h3 receptors mixed Inverse Agonism Agonism in vitro and partial Inverse Agonism in vivo
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: F. Gbahou, E. Davenas, S. Morisset, J.- ArrangAbstract:We previously suggested that therapeutic effects of betahistine in vestibular disorders result from its antagonist properties at histamine H(3) receptors (H(3)Rs). However, H(3)Rs exhibit constitutive activity, and most H(3)R antagonists act as Inverse agonists. Here, we have investigated the effects of betahistine at recombinant H(3)R isoforms. On inhibition of cAMP formation and [(3)H]arachidonic acid release, betahistine behaved as a nanomolar Inverse agonist and a micromolar agonist. Both effects were suppressed by pertussis toxin, were found at all isoforms tested, and were not detected in mock cells, confirming interactions at H(3)Rs. The Inverse agonist potency of betahistine and its affinity on [(125)I]iodoproxyfan binding were similar in rat and human. We then investigated the effects of betahistine on histamine neuron activity by measuring tele-methylhistamine (t-MeHA) levels in the brains of mice. Its acute intraperitoneal administration increased t-MeHA levels with an ED(50) of 0.4 mg/kg, indicating Inverse Agonism. At higher doses, t-MeHA levels gradually returned to basal levels, a profile probably resulting from Agonism. After acute oral administration, betahistine increased t-MeHA levels with an ED(50) of 2 mg/kg, a rightward shift probably caused by almost complete first-pass metabolism. In each case, the maximal effect of betahistine was lower than that of ciproxifan, indicating partial Inverse Agonism. After an oral 8-day treatment, the only effective dose of betahistine was 30 mg/kg, indicating that a tolerance had developed. These data strongly suggest that therapeutic effects of betahistine result from an enhancement of histamine neuron activity induced by Inverse Agonism at H(3) autoreceptors.
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Effects of Betahistine at Histamine H3 Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: F. Gbahou, E. Davenas, S. Morisset, J.- ArrangAbstract:We previously suggested that therapeutic effects of betahistine in vestibular disorders result from its antagonist properties at histamine H3 receptors (H3Rs). However, H3Rs exhibit constitutive activity and most H3R antagonists act as Inverse agonists. Here, we have first investigated the effects of betahistine at recombinant H3R isoforms. On inhibition of cAMP formation and [3H]arachidonic acid release, betahistine behaved as a nanomolar Inverse agonist and a micromolar agonist. Both effects were suppressed by pertussis toxin, were found at all isoforms tested, and were not detected in mock cells, confirming interactions at H3Rs. The Inverse agonist potency of betahistine and its affinity on [125I]iodoproxyfan binding were similar in rat and human. We have then investigated the effects of betahistine on histamine neuron activity, by measuring tele-methylhistamine (t-MeHA) levels in the brain of mice. Its acute intraperitoneal administration increased t-MeHA levels with an ED50 of 0.4 mg/kg, indicating Inverse Agonism. At higher doses, t-MeHA levels gradually returned to basal levels, a profile probably resulting from Agonism. After acute oral administration, betahistine increased t-MeHA levels with an ED50 of 2 mg/kg, a rightward shift likely due to almost complete first-pass metabolism. In each case, the maximal effect of betahistine was lower than that of ciproxifan, indicating partial Inverse Agonism. After an oral 8-day treatment, the only effective dose of betahistine was of 30 mg/kg, indicating that a tolerance had developed. These data strongly suggest that therapeutic effects of betahistine result from an enhancement of histamine neuron activity induced by Inverse Agonism at H3 autoreceptors.
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Effects of Betahistine at Histamine H3 Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo
The Journal of pharmacology and experimental therapeutics, 2010Co-Authors: F. Gbahou, E. Davenas, S. Morisset, J.- ArrangAbstract:We previously suggested that therapeutic effects of betahistine in vestibular disorders result from its antagonist properties at histamine H(3) receptors (H(3)Rs). However, H(3)Rs exhibit constitutive activity, and most H(3)R antagonists act as Inverse agonists. Here, we have investigated the effects of betahistine at recombinant H(3)R isoforms. On inhibition of cAMP formation and [(3)H]arachidonic acid release, betahistine behaved as a nanomolar Inverse agonist and a micromolar agonist. Both effects were suppressed by pertussis toxin, were found at all isoforms tested, and were not detected in mock cells, confirming interactions at H(3)Rs. The Inverse agonist potency of betahistine and its affinity on [(125)I]iodoproxyfan binding were similar in rat and human. We then investigated the effects of betahistine on histamine neuron activity by measuring tele-methylhistamine (t-MeHA) levels in the brains of mice. Its acute intraperitoneal administration increased t-MeHA levels with an ED(50) of 0.4 mg/kg, indicating Inverse Agonism. At higher doses, t-MeHA levels gradually returned to basal levels, a profile probably resulting from Agonism. After acute oral administration, betahistine increased t-MeHA levels with an ED(50) of 2 mg/kg, a rightward shift probably caused by almost complete first-pass metabolism. In each case, the maximal effect of betahistine was lower than that of ciproxifan, indicating partial Inverse Agonism. After an oral 8-day treatment, the only effective dose of betahistine was 30 mg/kg, indicating that a tolerance had developed. These data strongly suggest that therapeutic effects of betahistine result from an enhancement of histamine neuron activity induced by Inverse Agonism at H(3) autoreceptors.
Kelly A. Berg - One of the best experts on this subject based on the ideXlab platform.
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Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity.
The International Journal of Neuropsychopharmacology, 2018Co-Authors: Kelly A. Berg, William P. ClarkeAbstract:: Constitutive receptor activity/Inverse Agonism and functional selectivity/biased Agonism are 2 concepts in contemporary pharmacology that have major implications for the use of drugs in medicine and research as well as for the processes of new drug development. Traditional receptor theory postulated that receptors in a population are quiescent unless activated by a ligand. Within this framework ligands could act as agonists with various degrees of intrinsic efficacy, or as antagonists with zero intrinsic efficacy. We now know that receptors can be active without an activating ligand and thus display "constitutive" activity. As a result, a new class of ligand was discovered that can reduce the constitutive activity of a receptor. These ligands produce the opposite effect of an agonist and are called Inverse agonists. The second topic discussed is functional selectivity, also commonly referred to as biased Agonism. Traditional receptor theory also posited that intrinsic efficacy is a single drug property independent of the system in which the drug acts. However, we now know that a drug, acting at a single receptor subtype, can have multiple intrinsic efficacies that differ depending on which of the multiple responses coupled to a receptor is measured. Thus, a drug can be simultaneously an agonist, an antagonist, and an Inverse agonist acting at the same receptor. This means that drugs have an additional level of selectivity (signaling selectivity or "functional selectivity") beyond the traditional receptor selectivity. Both Inverse Agonism and functional selectivity need to be considered when drugs are used as medicines or as research tools.
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Atypical antipsychotics and Inverse Agonism at 5-HT 2 receptors
Current pharmaceutical design, 2015Co-Authors: Laura C. Sullivan, William P. Clarke, Kelly A. BergAbstract:It is now well accepted that receptors can regulate cellular signaling pathways in the absence of a stimulating ligand, and Inverse agonists can reduce this ligand-independent or "constitutive" receptor activity. Both the serotonin 5-HT2A and 5-HT2C receptors have demonstrated constitutive receptor activity in vitro and in vivo. Each has been identified as a target for treatment of schizophrenia. Further, most, if not all, atypical antipsychotic drugs have Inverse agonist properties at both 5-HT2A and 5-HT2C receptors. This paper describes our current knowledge of Inverse Agonism of atypical antipsychotics at 5-HT2A/2C receptor subtypes in vitro and in vivo. Exploiting Inverse agonist properties of APDs may provide new avenues for drug development.
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Inverse Agonism at serotonin and cannabinoid receptors.
Progress in molecular biology and translational science, 2010Co-Authors: Vincent J. Aloyo, William P. Clarke, Kelly A. Berg, Umberto Spampinato, John A HarveyAbstract:Abstract Contemporary receptor theory was developed to account for the existence of constitutive activity, as defined by the presence of receptor signaling in the absence of any ligand. In vitro studies with a variety of cell types have revealed the existence of constitutive activity and Inverse Agonism at a large number of receptors and also additional complexities of ligand–receptor interactions. Thus, ligands acting at a constitutively active receptor can act as agonists, antagonists, and/or Inverse agonists, and these pharmacological characteristics can differ for an individual ligand depending upon the receptor response measured and the physiological state of the system under study. Studies with a variety of cell types have established that the serotonin 5-HT2A and 5-HT2C receptors and the cannabinoid CB1 receptor demonstrate constitutive activity and Inverse Agonism in vitro. Serotonin and cannabinoid receptors are involved in a large number of physiological and behavioral functions. The possible existence of constitutive activity and Inverse Agonism at these receptors in vivo would provide new avenues for drug development. Recent studies have provided compelling evidence that both the serotonin 5-HT2A and 5-HT2C receptors and cannabinoid CB1 receptor demonstrate Inverse Agonism and constitutive activity also in vivo. This chapter describes our current knowledge of constitutive activity in vitro and then examines the evidence for constitutive activity in vivo.
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Current status of Inverse Agonism at serotonin2A (5-HT2A) and 5-HT2C receptors.
Pharmacology & therapeutics, 2008Co-Authors: Vincent J. Aloyo, William P. Clarke, Kelly A. Berg, Umberto Spampinato, John A HarveyAbstract:Contemporary receptor theory was developed to account for the existence of constitutive activity, as defined by the presence of receptor signaling in the absence of any ligand. Thus, ligands acting at a constitutively active receptor, can act as agonists, antagonists, and Inverse agonists. In vitro studies have also revealed the complexity of ligand/receptor interactions including agonist-directed stimulus trafficking, a finding that has led to multi-active state models of receptor function. Studies with a variety of cell types have established that the serotonin 5-HT(2A) and 5-HT(2C) receptors also demonstrate constitutive activity and Inverse Agonism. However, until recently, there has been no evidence to suggest that these receptors also demonstrate constitutive activity and hence reveal Inverse agonist properties of ligands in vivo. This paper describes our current knowledge of constitutive activity in vitro and then examines the evidence for constitutive activity in vivo. Both the serotonin 5-HT(2A) and 5-HT(2C) receptors are involved in a number of physiological and behavioral functions and are the targets for treatment of schizophrenia, anxiety, weight control, Parkinsonism, and other disorders. The existence of constitutive activity at these receptors in vivo, along with the possibility of Inverse Agonism, provides new avenues for drug development.
