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Pier Andrea Borea - One of the best experts on this subject based on the ideXlab platform.
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Binding Thermodynamic Characteristics of Adenosine Receptor Ligands
The Adenosine Receptors, 2018Co-Authors: Fabrizio Vincenzi, Katia Varani, Pier Andrea BoreaAbstract:Receptor Binding thermodynamics is a powerful tool to gain deep insight, at the molecular level, of the events that occur during Drug-Receptor interactions. This chapter focuses on the determination of thermodynamic parameters based on the van’t Hoff analysis as a traditional method to discover the enthalpic and entropic contributions during Drug-Receptor Binding. Thermodynamic parameters of adenosine Receptor ligands such as standard free energy (ΔG°), standard enthalpy (ΔH°), and standard entropy (ΔS°) are reported, discussed, and compared with those observed for other membrane Receptors investigated from a thermodynamic point of view. The available thermodynamic data are evaluated in terms of two important physical phenomena, the thermodynamic discrimination and enthalpy-entropy compensation. Thermodynamic parameters obtained by means of radioligand Binding studies for adenosine Receptor ligands, as well as for other classes of Receptors, represent relevant information to the Drug design and optimization providing a benefit to the Drug discovery process.
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Thermodynamic Analysis in Drug–Receptor Binding: The A3 Adenosine Receptor
A3 Adenosine Receptors from Cell Biology to Pharmacology and Therapeutics, 2009Co-Authors: Pier Andrea Borea, Stefania Gessi, Stefania Merighi, Katia VaraniAbstract:Receptor Binding thermodynamics is a powerful tool to gain deep insight, at the molecular level, of the events which occur during Drug–Receptor interactions. This paper deals with the study of the A3 adenosine Receptors in the general scenario of all Receptors studied so far from this point of view. Thermodynamic parameters, standard free energy (ΔG°), standard enthalpy (ΔH°) and standard entropy (ΔS°) of the A3 adenosine Receptor Binding equilibrium are reported, discussed and compared with those observed for membrane Receptors thermodynamically investigated. As for available thermodynamic data of all G-protein coupled Receptors (GPCRs) and ligand-gated ion channels Receptors (LGICRs) are reported and discussed in terms of two important physical phenomena, the thermodynamic discrimination and enthalpy–entropy compensation. Thermodynamic data of A3 adenosine Receptors will be compared with those obtained in different cell systems for A1, A2A and A2B Receptors.
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Binding thermodynamics as a tool to investigate the mechanisms of Drug Receptor interactions thermodynamics of cytoplasmic steroid nuclear Receptors in comparison with membrane Receptors
Journal of Medicinal Chemistry, 2005Co-Authors: Paola Gilli, Gastone Gilli, Pier Andrea Borea, Katia Varani, And Angelo Scatturin, Alessandro DalpiazAbstract:Drug−Receptor Binding thermodynamics has proved to be a valid tool for pharmacological and pharmaceutical characterization of molecular mechanisms of Receptor-recognition phenomena. The large number of membrane Receptors so far studied has led to the discovery of enthalpy−entropy compensation effects in Drug−Receptor Binding and discrimination between agonists and antagonists by thermodynamic methods. Since a single thermodynamic study on cytoplasmic Receptors was known, this paper reports on Binding thermodynamics of estradiol, ORG2058, and R1881 bound to estrogen, progesterone, and androgen steroid/nuclear Receptors, respectively, as determined by variable-temperature Binding constant measurements. The Binding at 25 °C appears enthalpy/entropy-driven (−53.0 ≤ ΔG° ≤ −48.6, −34.5 ≤ ΔH°≤ −19.9 kJ/mol, 0.057 ≤ ΔS° ≤ 0.111, and −2.4 ≤ ΔCp° ≤ −1.7 kJ mol-1 K-1) and is interpreted in terms of hydrophobic and hydrogen-bonded specific interactions. Results obtained for cytoplasmic Receptors are extensively compa...
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Binding thermodynamics as a tool to investigate the mechanisms of Drug-Receptor interactions: thermodynamics of cytoplasmic steroid/nuclear Receptors in comparison with membrane Receptors.
Journal of Medicinal Chemistry, 2005Co-Authors: Paola Gilli, Gastone Gilli, Pier Andrea Borea, Katia Varani, And Angelo Scatturin, Alessandro DalpiazAbstract:Drug−Receptor Binding thermodynamics has proved to be a valid tool for pharmacological and pharmaceutical characterization of molecular mechanisms of Receptor-recognition phenomena. The large number of membrane Receptors so far studied has led to the discovery of enthalpy−entropy compensation effects in Drug−Receptor Binding and discrimination between agonists and antagonists by thermodynamic methods. Since a single thermodynamic study on cytoplasmic Receptors was known, this paper reports on Binding thermodynamics of estradiol, ORG2058, and R1881 bound to estrogen, progesterone, and androgen steroid/nuclear Receptors, respectively, as determined by variable-temperature Binding constant measurements. The Binding at 25 °C appears enthalpy/entropy-driven (−53.0 ≤ ΔG° ≤ −48.6, −34.5 ≤ ΔH°≤ −19.9 kJ/mol, 0.057 ≤ ΔS° ≤ 0.111, and −2.4 ≤ ΔCp° ≤ −1.7 kJ mol-1 K-1) and is interpreted in terms of hydrophobic and hydrogen-bonded specific interactions. Results obtained for cytoplasmic Receptors are extensively compa...
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can thermodynamic measurements of Receptor Binding yield information on Drug affinity and efficacy
Biochemical Pharmacology, 2000Co-Authors: Pier Andrea Borea, Paola Gilli, Katia Varani, Alessandro Dalpiaz, Gastone GilliAbstract:Abstract The present commentary surveys the methods for obtaining the thermodynamic parameters of the Drug–Receptor Binding equilibrium, ΔG°, ΔH°, ΔS°, and ΔC°p (standard free energy, enthalpy, entropy, and heat capacity, respectively). Moreover, it reviews the available thermodynamic data for the Binding of agonists and antagonists to several G-protein coupled Receptors (GPCRs) and ligand-gated ion channel Receptors (LGICRs). In particular, thermodynamic data for five GPCRs (β-adrenergic, adenosine A1, adenosine A2A, dopamine D2, and 5-HT1A) and four LGICRs (glycine, GABAA, 5-HT3, and nicotinic) have been collected and analyzed. Among these Receptor systems, seven (three GPCRs and all LGICRs) show “thermodynamic agonist–antagonist discrimination”: when the agonist Binding to a given Receptor is entropy-driven, the Binding of its antagonist is enthalpy-driven, or vice versa. A scatter plot of all entropy versus enthalpy values of the database gives a regression line with the equation TΔS° (kJ mol−1; T = 298.15 K) = 40.3 (± 0.7) + 1.00 (±0.01) ΔH° (kJ mol−1); N = 184; r = 0.981; P
David E Shaw - One of the best experts on this subject based on the ideXlab platform.
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molecular determinants of Drug Receptor Binding kinetics
Drug Discovery Today, 2013Co-Authors: David W Borhani, Ron O Dror, David E ShawAbstract:It is increasingly appreciated that the rates at which Drugs associate with and dissociate from Receptors — the Binding kinetics — directly impact Drug efficacy and safety. The molecular determinants of Drug–Receptor Binding kinetics remain poorly understood, however, especially when compared with the well-known factors that affect Binding affinity. The rational modulation of kinetics during lead optimization thus remains challenging. We review some of the key factors thought to control Drug–Receptor Binding kinetics at the molecular level — molecular size, conformational fluctuations, electrostatic interactions and hydrophobic effects — and discuss several possible approaches for the rational design of Drugs with desired Binding kinetics.
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Molecular determinants of Drug–Receptor Binding kinetics
Drug Discovery Today, 2013Co-Authors: David W Borhani, Ron O Dror, David E ShawAbstract:It is increasingly appreciated that the rates at which Drugs associate with and dissociate from Receptors — the Binding kinetics — directly impact Drug efficacy and safety. The molecular determinants of Drug–Receptor Binding kinetics remain poorly understood, however, especially when compared with the well-known factors that affect Binding affinity. The rational modulation of kinetics during lead optimization thus remains challenging. We review some of the key factors thought to control Drug–Receptor Binding kinetics at the molecular level — molecular size, conformational fluctuations, electrostatic interactions and hydrophobic effects — and discuss several possible approaches for the rational design of Drugs with desired Binding kinetics.
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Pathway and mechanism of Drug Binding to G-protein-coupled Receptors
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Ron O Dror, David W Borhani, Daniel H. Arlow, Paul Maragakis, Yibing Shan, Huafeng Xu, David E ShawAbstract:How Drugs bind to their Receptors—from initial association, through Drug entry into the Binding pocket, to adoption of the final bound conformation, or “pose”—has remained unknown, even for G-protein-coupled Receptor modulators, which constitute one-third of all marketed Drugs. We captured this pharmaceutically critical process in atomic detail using the first unbiased molecular dynamics simulations in which Drug molecules spontaneously associate with G-protein-coupled Receptors to achieve final poses matching those determined crystallographically. We found that several beta blockers and a beta agonist all traverse the same well-defined, dominant pathway as they bind to the β1- and β2-adrenergic Receptors, initially making contact with a vestibule on each Receptor’s extracellular surface. Surprisingly, association with this vestibule, at a distance of 15 Å from the Binding pocket, often presents the largest energetic barrier to Binding, despite the fact that subsequent entry into the Binding pocket requires the Receptor to deform and the Drug to squeeze through a narrow passage. The early barrier appears to reflect the substantial dehydration that takes place as the Drug associates with the vestibule. Our atomic-level description of the Binding process suggests opportunities for allosteric modulation and provides a structural foundation for future optimization of Drug–Receptor Binding and unBinding rates.
Gastone Gilli - One of the best experts on this subject based on the ideXlab platform.
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Binding thermodynamics as a tool to investigate the mechanisms of Drug Receptor interactions thermodynamics of cytoplasmic steroid nuclear Receptors in comparison with membrane Receptors
Journal of Medicinal Chemistry, 2005Co-Authors: Paola Gilli, Gastone Gilli, Pier Andrea Borea, Katia Varani, And Angelo Scatturin, Alessandro DalpiazAbstract:Drug−Receptor Binding thermodynamics has proved to be a valid tool for pharmacological and pharmaceutical characterization of molecular mechanisms of Receptor-recognition phenomena. The large number of membrane Receptors so far studied has led to the discovery of enthalpy−entropy compensation effects in Drug−Receptor Binding and discrimination between agonists and antagonists by thermodynamic methods. Since a single thermodynamic study on cytoplasmic Receptors was known, this paper reports on Binding thermodynamics of estradiol, ORG2058, and R1881 bound to estrogen, progesterone, and androgen steroid/nuclear Receptors, respectively, as determined by variable-temperature Binding constant measurements. The Binding at 25 °C appears enthalpy/entropy-driven (−53.0 ≤ ΔG° ≤ −48.6, −34.5 ≤ ΔH°≤ −19.9 kJ/mol, 0.057 ≤ ΔS° ≤ 0.111, and −2.4 ≤ ΔCp° ≤ −1.7 kJ mol-1 K-1) and is interpreted in terms of hydrophobic and hydrogen-bonded specific interactions. Results obtained for cytoplasmic Receptors are extensively compa...
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Binding thermodynamics as a tool to investigate the mechanisms of Drug-Receptor interactions: thermodynamics of cytoplasmic steroid/nuclear Receptors in comparison with membrane Receptors.
Journal of Medicinal Chemistry, 2005Co-Authors: Paola Gilli, Gastone Gilli, Pier Andrea Borea, Katia Varani, And Angelo Scatturin, Alessandro DalpiazAbstract:Drug−Receptor Binding thermodynamics has proved to be a valid tool for pharmacological and pharmaceutical characterization of molecular mechanisms of Receptor-recognition phenomena. The large number of membrane Receptors so far studied has led to the discovery of enthalpy−entropy compensation effects in Drug−Receptor Binding and discrimination between agonists and antagonists by thermodynamic methods. Since a single thermodynamic study on cytoplasmic Receptors was known, this paper reports on Binding thermodynamics of estradiol, ORG2058, and R1881 bound to estrogen, progesterone, and androgen steroid/nuclear Receptors, respectively, as determined by variable-temperature Binding constant measurements. The Binding at 25 °C appears enthalpy/entropy-driven (−53.0 ≤ ΔG° ≤ −48.6, −34.5 ≤ ΔH°≤ −19.9 kJ/mol, 0.057 ≤ ΔS° ≤ 0.111, and −2.4 ≤ ΔCp° ≤ −1.7 kJ mol-1 K-1) and is interpreted in terms of hydrophobic and hydrogen-bonded specific interactions. Results obtained for cytoplasmic Receptors are extensively compa...
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can thermodynamic measurements of Receptor Binding yield information on Drug affinity and efficacy
Biochemical Pharmacology, 2000Co-Authors: Pier Andrea Borea, Paola Gilli, Katia Varani, Alessandro Dalpiaz, Gastone GilliAbstract:Abstract The present commentary surveys the methods for obtaining the thermodynamic parameters of the Drug–Receptor Binding equilibrium, ΔG°, ΔH°, ΔS°, and ΔC°p (standard free energy, enthalpy, entropy, and heat capacity, respectively). Moreover, it reviews the available thermodynamic data for the Binding of agonists and antagonists to several G-protein coupled Receptors (GPCRs) and ligand-gated ion channel Receptors (LGICRs). In particular, thermodynamic data for five GPCRs (β-adrenergic, adenosine A1, adenosine A2A, dopamine D2, and 5-HT1A) and four LGICRs (glycine, GABAA, 5-HT3, and nicotinic) have been collected and analyzed. Among these Receptor systems, seven (three GPCRs and all LGICRs) show “thermodynamic agonist–antagonist discrimination”: when the agonist Binding to a given Receptor is entropy-driven, the Binding of its antagonist is enthalpy-driven, or vice versa. A scatter plot of all entropy versus enthalpy values of the database gives a regression line with the equation TΔS° (kJ mol−1; T = 298.15 K) = 40.3 (± 0.7) + 1.00 (±0.01) ΔH° (kJ mol−1); N = 184; r = 0.981; P
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enthalpy entropy compensation in Drug Receptor Binding
The Journal of Physical Chemistry, 1994Co-Authors: Paola Gilli, Valeria Ferretti, Gastone Gilli, Pier Andrea BoreaAbstract:The thermodynamic parameters (ΔG o , ΔH o , ΔS o ) of the Drug-Receptor Binding equilibrium derived from equilibrium constant measurements at different temperatures and van't Hoff plots are reviewed. The analysis involves 186 independent experiments performed on 136 ligands Binding to 10 biological Receptors and, for comparison, to DNA and to two different enzymes. ΔH o and ΔS o values correlate according to the regression equation ΔH o (kcal mol -1 )=-9.5+27845 o (kcal K -1 mol -1 ) with a correlation coefficient of 0.981. The correlating equation is of the form ΔH o =βΔS o and is expected for a case of enthalpy-entropy compensation with a compensation temperature β=278 K
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stereochemistry of benzodiazepine Receptor ligands possible role of c h x interactions in Drug Receptor Binding and crystal structures of cl218 872 zopiclone and dmcm
Journal of The Chemical Society-perkin Transactions 1, 1990Co-Authors: Valerio Bertolasi, Valeria Ferretti, Gastone Gilli, Pier Andrea BoreaAbstract:The crystal structures of three benzodiazepine (BDZ)-Receptor ligands, i.e. CL218–872, Zopiclone and DMCM, are reported. CL218-872 crystallizes in the space group Pccn with a= 22.624(2), b= 13.073(2), c= 8.385(1)A. 1160 reflections with I > 3σ(I) were used in the refinement. The structure was solved by direct methods and refined by weighted full-matrix least-squares with anisotropic non-H and isotropic H atoms to R= 0.038. Zopiclone crystallizes in the space group P212121 with a= 5.567(3), b= 8.852(2), c= 35.677(17)A. 915 reflections with I > 1.5σ(I) were used in the refinement. The structure was solved by direct methods and refined by weighted full-matrix least-squares with anisotropic non-H and calculated H atoms to R= 0.060. DMCM crystallizes in the space group P21/n with a= 13.801 (3), b= 10.980(2), c= 10.620(2)A, β= 103.81(2)°. 1 857 reflections with I > 2σ(I) were used in the refinement. The structure was solved by direct methods and refined by weighted full-matrix least-squares with anisotropic non-H and isotropic H atoms to R= 0.044.A detailed analysis of the hydrogen bonds (HB) which exist in the packing of the three crystals has been carried out in order to understand the role played by hydrogen-bond interactions in the mechanism of action in Drug-Receptor Binding. The shortage of typical HB donor groups causes, in the structures examined, the occurrence of an unusual number of short C–H ⋯ X (X = O,N,F) interactions, where all hydrogens involved possess a partial positive charge, i.e. a somewhat acidic character. This fact can be an indication of the importance of such interactions, normally neglected. It is also shown, mainly by calculation of the electrostatic potential spanned by the single molecules, that the N–N group of the triazole ring in CL218–872 can play the role usually played by the strong acceptor CO group present in almost all BDZ-Receptor ligands.
Shizuo Yamada - One of the best experts on this subject based on the ideXlab platform.
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Basic and clinical aspects of antimuscarinic agents used to treat overactive bladder
Pharmacology & Therapeutics, 2018Co-Authors: Shizuo Yamada, Saori Nishijima, Katsumi Kadekawa, Kimio SugayaAbstract:Abstract Antimuscarinic agents are now widely used as the pharmacological therapy for overactive bladder (OAB) because neuronal (parasympathetic nerve) and non-neuronal acetylcholine play a significant role for the bladder function. In this review, we will highlight basic and clinical aspects of eight antimuscarinic agents (oxybutynin, propiverine, tolterodine, solifenacin, darifenacin, trospium, imidafenacin, and fesoterodine) clinically used to treat urinary dysfunction in patients with OAB. The basic pharmacological characteristics of these eight antimuscarinic agents include muscarinic Receptor subtype selectivity, functional bladder selectivity, and muscarinic Receptor Binding in the bladder and other tissues. The measurement of Drug-Receptor Binding after oral administration of these agents allows for clearer understanding of bladder selectivity by the integration of pharmacodynamics and pharmacokinetics under in vivo conditions. Their central nervous system (CNS) penetration potentials are also discussed in terms of the feasibility of impairments in memory and cognitive function in elderly patients with OAB. The clinical aspects of efficacy focus on improvements in the daytime urinary frequency, nocturia, bladder capacity, the frequency of urgency, severity of urgency, number of incontinence episodes, OAB symptom score, and quality of life (QOL) score by antimuscarinic agents in patients with OAB. The safety of and adverse events caused by treatments with antimuscarinic agents such as dry mouth, constipation, blurred vision, erythema, fatigue, increased sweating, urinary retention, and CNS adverse events are discussed. A dose-dependent relationship was observed with adverse events, because the risk ratio generally increased with elevations in the Drug dose of antimuscarinic agents. Side effect profiles may be additive to or contraindicated by other medications.
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Integration of Pharmacokinetics and Pharmacodynamics Based on the in Vivo Analysis of Drug-Receptor Binding
Yakugaku Zasshi-journal of The Pharmaceutical Society of Japan, 2015Co-Authors: Shizuo YamadaAbstract:As I was deeply interested in the effects of Drugs on the human body, I chose pharmacology as the subject of special study when I became a 4th year student at Shizuoka College of Pharmacy. I studied abroad as a postdoctoral fellow for two years, from 1978, under the tutelage of Professor Henry I. Yamamura (pharmacology) in the College of Medicine at the University of Arizona, USA. He taught me a variety of valuable skills such as the radioReceptor Binding assay, which represented the most advanced technology developed in the US at that time. After returning home, I engaged in clarifying Receptor abnormalities in pathological conditions, as well as in Drug action mechanisms, by making the best use of this radioReceptor Binding assay. In 1989, following the founding of the University of Shizuoka, I was invited by Professor Ryohei Kimura to join the Department of Pharmacokinetics. This switch in discipline provided a good opportunity for me to broaden my perspectives in pharmaceutical sciences. I worked on evaluating Drug-Receptor Binding in vivo as a combined index for pharmacokinetics and pharmacological effect manifestation, with the aim of bridging pharmacology and pharmacokinetics. In fact, by focusing on data from in vivo Receptor Binding, it became possible to clearly rationalize the important consideration of Drug dose-concentration-action relationships, and to study quantitative and kinetic analyses of relationships among pharmacokinetics, Receptor Binding and pharmacological effects. Based on this concept, I was able to demonstrate the utility of dynamic analyses of Drug-Receptor Binding in Drug discovery, Drug fostering, and the proper use of pharmacokinetics with regard to many Drugs.
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characterization of bladder selectivity of antimuscarinic agents on the basis of in vivo Drug Receptor Binding
International Neurourology Journal, 2012Co-Authors: Shizuo Yamada, Shiori Kuraoka, Ayaka OsanoAbstract:The in vivo muscarinic Receptor Binding of antimuscarinic agents (oxybutynin, solifenacin, tolterodine, and imidafenacin) used to treat urinary dysfunction in patients with overactive bladder is reviewed. Transdermal administration of oxybutynin in rats leads to significant Binding of muscarinic Receptors in the bladder without long-term Binding in the submaxillary gland and the abolishment of salivation evoked by oral oxybutynin. Oral solifenacin shows significant and long-lasting Binding to muscarinic Receptors in mouse tissues expressing the M3 subtype. Oral tolterodine binds more selectively to muscarinic Receptors in the bladder than in the submaxillary gland in mice. The muscarinic Receptor Binding of oral imidafenacin in rats is more selective and longer-lasting in the bladder than in other tissues such as the submaxillary gland, heart, colon, lung, and brain, suggesting preferential muscarinic Receptor Binding in the bladder. In vivo quantitative autoradiography with (+)N-[11C]methyl-3-piperidyl benzilate in rats shows significant occupancy of brain muscarinic Receptors with the intravenous injection of oxybutynin, solifenacin, and tolterodine. The estimated in vivo selectivity in brain is significantly greater for solifenacin and tolterodine than for oxybutynin. Imidafenacin occupies few brain muscarinic Receptors. Similar findings for oral oxybutynin were observed with positron emission tomography in conscious rhesus monkeys with a significant disturbance of short-term memory. The newer generation of antimuscarinic agents may be advantageous in terms of bladder selectivity after systemic administration.
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α1-Adrenoceptors and muscarinic Receptors in voiding function – Binding characteristics of therapeutic agents in relation to the pharmacokinetics
British Journal of Clinical Pharmacology, 2011Co-Authors: Shizuo Yamada, Hideo TsukadaAbstract:In vivo and ex vivo Binding of α1-adrenoceptor and muscarinic Receptors involved in voiding function is reviewed with therapeutic agents (α1-adrenoceptor antagonists: prazosin, tamsulosin and silodosin; and muscarinic Receptor antagonists: oxybutynin, tolterodine, solifenacin, propiverine, imiafenacin and darifenacin) in lower urinary tract symptoms. This approach allows estimation of the inhibition of a well-characterized selective (standard) radioligand by unlabelled potential Drugs or direct measurement of the distribution and Receptor Binding of a standard radioligand or radiolabelled form of a novel Drug. In fact, these studies could be conducted in various tissues from animals pretreated with radioligands and/or unlabelled novel Drugs, by conventional radioligand Binding assay, radioactivity measurement, autoradiography and positron emission tomography. In vivo and ex vivo Receptor Binding with α1-adrenoceptor antagonists and muscarinic Receptor antagonists have been proved to be useful in predicting the potency, organ selectivity and duration of action of Drugs in relation to their pharmacokinetics. Such evaluations of Drug–Receptor Binding reveal that adverse effects could be avoided by the use of new α1-adrenoceptor antagonists and muscarinic Receptor antagonists for the treatment of lower urinary tract symptoms. Thus, the comparative analysis of α1-adrenoceptor and muscarinic Receptor Binding characteristics in the lower urinary tract and other tissues after systemic administration of therapeutic agents allows the rationale for their pharmacological characteristics from the integrated viewpoint of pharmacokinetics and pharmacodynamics. The current review emphasizes the usefulness of in vivo and ex vivo Receptor Binding in the discovery and development of novel Drugs for the treatment of not only urinary dysfunction but also other disorders.
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the forefront for novel therapeutic agents based on the pathophysiology of lower urinary tract dysfunction bladder selectivity based on in vivo Drug Receptor Binding characteristics of antimuscarinic agents for treatment of overactive bladder
Journal of Pharmacological Sciences, 2010Co-Authors: Akira Yoshida, Tomomi Fujino, Shuji Maruyama, Yuko Taki, Shizuo YamadaAbstract:We have reviewed the Binding of antimuscarinic agents, used to treat urinary dysfunction in patients with overactive bladder, to muscarinic Receptors in target and non-target tissues in vivo. Transdermal administration of oxybutynin in rats led to significant Binding in the bladder without long-term Binding in the submaxillary gland and the abolishment of salivation evoked by oral oxybutynin. Oral solifenacin showed significant and long-lasting Binding to muscarinic Receptors in mouse tissues expressing the M3 subtype. Oral tolterodine bound more selectively to muscarinic Receptors in the bladder than in the submaxillary gland in mice. The muscarinic Receptor Binding activity of oral darifenacin in mice was shown to be pronounced and long-lasting in the bladder, submaxillary gland, and lung. In vivo quantitative autoradiography using (+)N-[11C]methyl-3-piperidyl benzilate in rats showed significant occupancy of brain muscarinic Receptors on intravenous injection of oxybutynin, propiverine, solifenacin, and tolterodine. The estimated in vivo bladder selectivity compared to brain was significantly greater for solifenacin and tolterodine than oxybutynin. Darifenacin occupied few brain muscarinic Receptors. Similar findings were also observed with positron emission tomography in conscious rhesus monkeys. The newer generation of antimuscarinic agents may be advantageous in the bladder selectivity after systemic administration.
Paola Gilli - One of the best experts on this subject based on the ideXlab platform.
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Binding thermodynamics as a tool to investigate the mechanisms of Drug-Receptor interactions: thermodynamics of cytoplasmic steroid/nuclear Receptors in comparison with membrane Receptors.
Journal of Medicinal Chemistry, 2005Co-Authors: Paola Gilli, Gastone Gilli, Pier Andrea Borea, Katia Varani, And Angelo Scatturin, Alessandro DalpiazAbstract:Drug−Receptor Binding thermodynamics has proved to be a valid tool for pharmacological and pharmaceutical characterization of molecular mechanisms of Receptor-recognition phenomena. The large number of membrane Receptors so far studied has led to the discovery of enthalpy−entropy compensation effects in Drug−Receptor Binding and discrimination between agonists and antagonists by thermodynamic methods. Since a single thermodynamic study on cytoplasmic Receptors was known, this paper reports on Binding thermodynamics of estradiol, ORG2058, and R1881 bound to estrogen, progesterone, and androgen steroid/nuclear Receptors, respectively, as determined by variable-temperature Binding constant measurements. The Binding at 25 °C appears enthalpy/entropy-driven (−53.0 ≤ ΔG° ≤ −48.6, −34.5 ≤ ΔH°≤ −19.9 kJ/mol, 0.057 ≤ ΔS° ≤ 0.111, and −2.4 ≤ ΔCp° ≤ −1.7 kJ mol-1 K-1) and is interpreted in terms of hydrophobic and hydrogen-bonded specific interactions. Results obtained for cytoplasmic Receptors are extensively compa...
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Binding thermodynamics as a tool to investigate the mechanisms of Drug Receptor interactions thermodynamics of cytoplasmic steroid nuclear Receptors in comparison with membrane Receptors
Journal of Medicinal Chemistry, 2005Co-Authors: Paola Gilli, Gastone Gilli, Pier Andrea Borea, Katia Varani, And Angelo Scatturin, Alessandro DalpiazAbstract:Drug−Receptor Binding thermodynamics has proved to be a valid tool for pharmacological and pharmaceutical characterization of molecular mechanisms of Receptor-recognition phenomena. The large number of membrane Receptors so far studied has led to the discovery of enthalpy−entropy compensation effects in Drug−Receptor Binding and discrimination between agonists and antagonists by thermodynamic methods. Since a single thermodynamic study on cytoplasmic Receptors was known, this paper reports on Binding thermodynamics of estradiol, ORG2058, and R1881 bound to estrogen, progesterone, and androgen steroid/nuclear Receptors, respectively, as determined by variable-temperature Binding constant measurements. The Binding at 25 °C appears enthalpy/entropy-driven (−53.0 ≤ ΔG° ≤ −48.6, −34.5 ≤ ΔH°≤ −19.9 kJ/mol, 0.057 ≤ ΔS° ≤ 0.111, and −2.4 ≤ ΔCp° ≤ −1.7 kJ mol-1 K-1) and is interpreted in terms of hydrophobic and hydrogen-bonded specific interactions. Results obtained for cytoplasmic Receptors are extensively compa...
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can thermodynamic measurements of Receptor Binding yield information on Drug affinity and efficacy
Biochemical Pharmacology, 2000Co-Authors: Pier Andrea Borea, Paola Gilli, Katia Varani, Alessandro Dalpiaz, Gastone GilliAbstract:Abstract The present commentary surveys the methods for obtaining the thermodynamic parameters of the Drug–Receptor Binding equilibrium, ΔG°, ΔH°, ΔS°, and ΔC°p (standard free energy, enthalpy, entropy, and heat capacity, respectively). Moreover, it reviews the available thermodynamic data for the Binding of agonists and antagonists to several G-protein coupled Receptors (GPCRs) and ligand-gated ion channel Receptors (LGICRs). In particular, thermodynamic data for five GPCRs (β-adrenergic, adenosine A1, adenosine A2A, dopamine D2, and 5-HT1A) and four LGICRs (glycine, GABAA, 5-HT3, and nicotinic) have been collected and analyzed. Among these Receptor systems, seven (three GPCRs and all LGICRs) show “thermodynamic agonist–antagonist discrimination”: when the agonist Binding to a given Receptor is entropy-driven, the Binding of its antagonist is enthalpy-driven, or vice versa. A scatter plot of all entropy versus enthalpy values of the database gives a regression line with the equation TΔS° (kJ mol−1; T = 298.15 K) = 40.3 (± 0.7) + 1.00 (±0.01) ΔH° (kJ mol−1); N = 184; r = 0.981; P
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Receptor Binding thermodynamics as a tool for linking Drug efficacy and affinity.
Farmaco, 1998Co-Authors: Pier Andrea Borea, Paola Gilli, Katia Varani, Stefania Gessi, Alessandro DalpiazAbstract:Abstract Determination of Drug-Receptor Binding constants (association, KA, or dissociation, KD=1/KA) by radiochemical specific Binding assays has proved to be an invaluable tool for screening of potential active Drugs. Simple determination of KA (or KD) values makes it possible, however, to calculate the standard free energy ΔG°=−RT ln KA=RT ln KD (T=298.15 K) of the Binding equilibrium but not that of its two components as defined by the Gibbs equation ΔG°=ΔH°−TΔS°, where ΔH° and ΔS° are the equilibrium standard enthalpy and entropy, respectively. This incomplete knowledge is highly inconvenient from a pure thermodynamic point of view as ΔH° and ΔS° carry much information on the details of the Drug–Receptor interaction and the interplay of both reaction partners with the solvent. In recent times it has been shown that the relative ΔH° and ΔS° magnitudes can often give a simple `in vitro' way for discriminating `the effect', that is the manner in which the Drug interferes with the signal transduction pathways. This particular effect, called `thermodynamic discrimination', results from the fact that Binding of antagonists may be enthalpy-driven and that of agonists entropy-driven, or vice versa. The first case of thermodynamic discrimination was reported for the β-adrenergic G-protein coupled Receptor (GPCR) and only recently has it been confirmed for adenosine A1 and A2a Receptors. Only very recently has the Binding thermodynamics of ligand-gated ion channel Receptors (LGICR) been investigated and data for four Receptors have been reported showing that all of them are thermodynamically discriminated. While it seems difficult at present to find a reasonable explanation for the thermodynamic discrimination phenomenon in GPCR, some hypotheses can be suggested for LGICR. Since global ΔH° and ΔS° values of the Binding process are expected to be heavily affected by rearrangements occurring in the solvent, thermodynamic discrimination in LGICR is at least logically understandable admitting that the observed ΔH° (and then ΔS°) values are determined by both specific Binding and abrupt variation of water-accessible Receptor surfaces consequent to the setting up of the channel opening.
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enthalpy entropy compensation in Drug Receptor Binding
The Journal of Physical Chemistry, 1994Co-Authors: Paola Gilli, Valeria Ferretti, Gastone Gilli, Pier Andrea BoreaAbstract:The thermodynamic parameters (ΔG o , ΔH o , ΔS o ) of the Drug-Receptor Binding equilibrium derived from equilibrium constant measurements at different temperatures and van't Hoff plots are reviewed. The analysis involves 186 independent experiments performed on 136 ligands Binding to 10 biological Receptors and, for comparison, to DNA and to two different enzymes. ΔH o and ΔS o values correlate according to the regression equation ΔH o (kcal mol -1 )=-9.5+27845 o (kcal K -1 mol -1 ) with a correlation coefficient of 0.981. The correlating equation is of the form ΔH o =βΔS o and is expected for a case of enthalpy-entropy compensation with a compensation temperature β=278 K
