Mathai Mammen - Academia.edu (original) (raw)
Papers by Mathai Mammen
Affinity capillary electrophoresis: Using capillary electrophoresis to study the interactions of proteins with ligands
Specificity of Induction of the vanA and vanB Operons in Vancomycin-Resistant Enterococci by Telavancin
Antimicrobial Agents and Chemotherapy, Jul 1, 2010
Optically Controlled Collisions Off Biological Objects
Quantum Electronics and Laser Science Conference, May 18, 1997
We have developed a new functional assay in which two mesoscale particles are caused to collide u... more We have developed a new functional assay in which two mesoscale particles are caused to collide using two independently controlled optical tweezers. This assay involved measurement of the probability of adhesion on collision. Since the components of the solution, the orientation, and the relative collision velocity are all under the user's control, this assay can mimic closely a range of
Characterization of Muscarinic M4 receptor‐G16a fusion protein in CHO‐K1 cells α
The FASEB Journal, 2006
THRX-160209 is a potent antagonist at the M 2 muscarinic acetylcholine (ACh) receptor subtype whi... more THRX-160209 is a potent antagonist at the M 2 muscarinic acetylcholine (ACh) receptor subtype which was designed using a multivalent strategy, simultaneously targeting the classical orthosteric site and a nearby site known to bind allosteric ligands. Here we describe three characteristics of THRX-160209 binding which are consistent with a multivalent interaction: (1) An apparent affinity of the multivalent ligand for the M 2 receptor subtype (apparent pK I = 9.51 + 0.22) which was several orders of magnitude greater than its two monovalent components (apparent pK I values < 6.0) (2) Specificity of THRX-160209 for the M 2 receptor subtype, as compared to the closely related M 4 (apparent pK I = 8.78 + 0.24) and M 1 , M 3 and M 5 receptors (apparent pK I values < 8.0) (3) Acceleration (> 10-fold) of the dissociation rate of tritium labeled THRX-160209 from M 2 receptors by competing monovalent ligands that are known to interact with either the orthosteric site (e.g. atropine) or a well-characterized, allosteric site (e.g. obidoxime) on the receptor. In complementary kinetic studies assessing allosteric modulation of the receptor, unlabeled THRX-160209 retarded dissociation of [ 3 H]NMS. The effects of THRX-160209 on retardation of [ 3 H]NMS dissociation were competitively inhibited by obidoxime, suggesting that obidoxime and THRX-160209 bind to an overlapping region coincident with other typical muscarinic allosteric agents, such as W84 and gallamine. Collectively, these data are consistent with the hypothesis that THRX-160209 binds in a multivalent manner to the M 2 receptor, simultaneously occupying the orthosteric and a spatially distinct, allosteric site.
Relationship between β2-Adrenoceptor Density and Bronchoprotection in Guinea Pigs Treated Acutely or Chronically with Indacaterol
C48. COPD: PHARMACOLOGICAL TREATMENT BETA AGONIST, 2009
Pharmacology Research & Perspectives, 2018
Revefenacin (TD‐4208) is a novel, long‐acting, and lung‐selective muscarinic cholinergic receptor... more Revefenacin (TD‐4208) is a novel, long‐acting, and lung‐selective muscarinic cholinergic receptor (mAChR) antagonist in development as a nebulized inhalation solution for the treatment of chronic obstructive pulmonary disease (COPD) patients. This study evaluated the pharmacology of revefenacin at human recombinant mAChRs and in airway tissues from rats, guinea pigs, and humans. At human recombinant mAChRs, revefenacin displayed high affinity (pKI = 8.2‐9.8) and behaved as a competitive antagonist (pKI, apparent = 9.4‐10.9) at the five human recombinant mAChRs. Kinetic studies demonstrated that revefenacin dissociated significantly slower from the hM3 (t1/2 = 82 minutes) compared to the hM2 (t1/2 = 6.9 minutes) mAChR at 37°C, thereby making it kinetically selective for the former subtype. Similarly, in functional studies, revefenacin‐mediated antagonism of acetylcholine (ACh)‐evoked calcium mobilization responses were reversed less rapidly at hM3 compared to the hM2 mAChR. In isolat...
Muscarinic Receptor Antagonists
Polyvalent presenter combinatorial libraries and their uses
Polymeric Conjugates Polyvalently Presenting an Agent for Therapy
Muscarinic receptor antagonists
Multibinding ligands containing such as amine, amide, ester, hydroxyl, carbamate, urea and/or imino functionality
Azabicycloalkane Compounds as Muscarinic Receptor Antagonists
Chronic obstructive pulmonary dusease; asthma
Methods for Identifying Novel Multimeric Agents That Modulate Receptors
Method for identifying a ligand for a biological substrate
Intermediates for use in the preparation of urea compounds having muscarinic receptor antagonist activity
Urea Compounds Having Muscarinic Receptor Antagonist Activity
Carbamate Derivatives Having Muscarinic Receptor Antagonist Activity
Method for identifying ligands for a biological substrate
Affinity capillary electrophoresis: Using capillary electrophoresis to study the interactions of proteins with ligands
Specificity of Induction of the vanA and vanB Operons in Vancomycin-Resistant Enterococci by Telavancin
Antimicrobial Agents and Chemotherapy, Jul 1, 2010
Optically Controlled Collisions Off Biological Objects
Quantum Electronics and Laser Science Conference, May 18, 1997
We have developed a new functional assay in which two mesoscale particles are caused to collide u... more We have developed a new functional assay in which two mesoscale particles are caused to collide using two independently controlled optical tweezers. This assay involved measurement of the probability of adhesion on collision. Since the components of the solution, the orientation, and the relative collision velocity are all under the user's control, this assay can mimic closely a range of
Characterization of Muscarinic M4 receptor‐G16a fusion protein in CHO‐K1 cells α
The FASEB Journal, 2006
THRX-160209 is a potent antagonist at the M 2 muscarinic acetylcholine (ACh) receptor subtype whi... more THRX-160209 is a potent antagonist at the M 2 muscarinic acetylcholine (ACh) receptor subtype which was designed using a multivalent strategy, simultaneously targeting the classical orthosteric site and a nearby site known to bind allosteric ligands. Here we describe three characteristics of THRX-160209 binding which are consistent with a multivalent interaction: (1) An apparent affinity of the multivalent ligand for the M 2 receptor subtype (apparent pK I = 9.51 + 0.22) which was several orders of magnitude greater than its two monovalent components (apparent pK I values < 6.0) (2) Specificity of THRX-160209 for the M 2 receptor subtype, as compared to the closely related M 4 (apparent pK I = 8.78 + 0.24) and M 1 , M 3 and M 5 receptors (apparent pK I values < 8.0) (3) Acceleration (> 10-fold) of the dissociation rate of tritium labeled THRX-160209 from M 2 receptors by competing monovalent ligands that are known to interact with either the orthosteric site (e.g. atropine) or a well-characterized, allosteric site (e.g. obidoxime) on the receptor. In complementary kinetic studies assessing allosteric modulation of the receptor, unlabeled THRX-160209 retarded dissociation of [ 3 H]NMS. The effects of THRX-160209 on retardation of [ 3 H]NMS dissociation were competitively inhibited by obidoxime, suggesting that obidoxime and THRX-160209 bind to an overlapping region coincident with other typical muscarinic allosteric agents, such as W84 and gallamine. Collectively, these data are consistent with the hypothesis that THRX-160209 binds in a multivalent manner to the M 2 receptor, simultaneously occupying the orthosteric and a spatially distinct, allosteric site.
Relationship between β2-Adrenoceptor Density and Bronchoprotection in Guinea Pigs Treated Acutely or Chronically with Indacaterol
C48. COPD: PHARMACOLOGICAL TREATMENT BETA AGONIST, 2009
Pharmacology Research & Perspectives, 2018
Revefenacin (TD‐4208) is a novel, long‐acting, and lung‐selective muscarinic cholinergic receptor... more Revefenacin (TD‐4208) is a novel, long‐acting, and lung‐selective muscarinic cholinergic receptor (mAChR) antagonist in development as a nebulized inhalation solution for the treatment of chronic obstructive pulmonary disease (COPD) patients. This study evaluated the pharmacology of revefenacin at human recombinant mAChRs and in airway tissues from rats, guinea pigs, and humans. At human recombinant mAChRs, revefenacin displayed high affinity (pKI = 8.2‐9.8) and behaved as a competitive antagonist (pKI, apparent = 9.4‐10.9) at the five human recombinant mAChRs. Kinetic studies demonstrated that revefenacin dissociated significantly slower from the hM3 (t1/2 = 82 minutes) compared to the hM2 (t1/2 = 6.9 minutes) mAChR at 37°C, thereby making it kinetically selective for the former subtype. Similarly, in functional studies, revefenacin‐mediated antagonism of acetylcholine (ACh)‐evoked calcium mobilization responses were reversed less rapidly at hM3 compared to the hM2 mAChR. In isolat...
Muscarinic Receptor Antagonists
Polyvalent presenter combinatorial libraries and their uses
Polymeric Conjugates Polyvalently Presenting an Agent for Therapy
Muscarinic receptor antagonists
Multibinding ligands containing such as amine, amide, ester, hydroxyl, carbamate, urea and/or imino functionality
Azabicycloalkane Compounds as Muscarinic Receptor Antagonists
Chronic obstructive pulmonary dusease; asthma
Methods for Identifying Novel Multimeric Agents That Modulate Receptors
Method for identifying a ligand for a biological substrate
Intermediates for use in the preparation of urea compounds having muscarinic receptor antagonist activity
Urea Compounds Having Muscarinic Receptor Antagonist Activity
Carbamate Derivatives Having Muscarinic Receptor Antagonist Activity
Method for identifying ligands for a biological substrate