3-Quinuclidinyl benzilate (BZ) ranks among incapacitating military warfare agents. It acts as a competitive inhibitor on muscarinic receptors leading to non-lethal mental impairment. The present study aimed to investigate toxicokinetics of BZ in rats. Moreover, BZ can be exploited to produce a pharmacological model of Alzheimer's disease; thus, this paper focuses mainly on the BZ distribution to the brain. Wistar rats were administered i.p. with BZ (2 and 10 mg/kg). The BZ concentration was determined using LC-MS/MS in plasma, urine, bile, brain, kidney and liver. The sample preparation was based on a solid phase extraction (liquids) or protein precipitation (organ homogenates). The plasma concentration peaked at 3 min (204.5 ± 55.4 and 2185.5 ± 465.4 ng/ml). The maximal concentration in the brain was reached several minutes later. Plasma elimination half-life was 67.9 ± 3.4 in the 2 mg/kg group and 96.6 ± 27.9 in the 10 mg/kg group. BZ concentrations remained steady in the brain, with slow elimination (t1/2 506.9 ± 359.5 min). Agent BZ is excreted mainly via the urine. Steady BZ concentration in the brain could explain the previously published duration of the significant impairment in passive avoidance tasks in rats after an injection of BZ.
- MeSH
- antagonisté muskarinových receptorů krev metabolismus toxicita moč MeSH
- chinuklidinylbenzilát krev metabolismus toxicita moč MeSH
- krysa rodu rattus MeSH
- metabolom MeSH
- moč MeSH
- mozek metabolismus MeSH
- potkani Wistar MeSH
- toxikokinetika MeSH
- žluč metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Allosteric modulators are ligands that bind to a site on the receptor that is spatially separated from the orthosteric binding site for the endogenous neurotransmitter. Allosteric modulators modulate the binding affinity, potency, and efficacy of orthosteric ligands. Muscarinic acetylcholine receptors are prototypical allosterically-modulated G-protein-coupled receptors. They are a potential therapeutic target for the treatment of psychiatric, neurologic, and internal diseases like schizophrenia, Alzheimer's disease, Huntington disease, type 2 diabetes, or chronic pulmonary obstruction. Here, we reviewed the progress made during the last decade in our understanding of their mechanisms of binding, allosteric modulation, and in vivo actions in order to understand the translational impact of studying this important class of pharmacological agents. We overviewed newly developed allosteric modulators of muscarinic receptors as well as new spin-off ideas like bitopic ligands combining allosteric and orthosteric moieties and photo-switchable ligands based on bitopic agents.
- MeSH
- agonisté muskarinových receptorů metabolismus MeSH
- alosterická regulace fyziologie MeSH
- antagonisté muskarinových receptorů metabolismus MeSH
- lidé MeSH
- ligandy MeSH
- receptory muskarinové metabolismus fyziologie MeSH
- receptory spřažené s G-proteiny MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Muscarinic receptors are known to play important biological roles and are drug targets for several human diseases. In a pilot study, novel muscarinic antagonists were synthesized and used as chemical probes to obtain additional information of the muscarinic pharmacophore. The design of these ligands made use of current orthosteric and allosteric models of drug-receptor interactions together with chemical motifs known to achieve muscarinic receptor selectivity. This approach has led to the discovery of several non-competitive muscarinic ligands that strongly bind at a secondary receptor site. These compounds were found to be non-competitive antagonists that completely abolished carbachol activation in functional assays. Several of these compounds antagonized functional response to carbachol with great potency at M1 and M4 than at the rest of receptor subtypes.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- alosterická regulace MeSH
- antagonisté muskarinových receptorů chemická syntéza chemie metabolismus MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- křečci praví MeSH
- lidé MeSH
- ligandy MeSH
- N-methylskopolamin chemická syntéza chemie metabolismus MeSH
- pilotní projekty MeSH
- protein - isoformy chemie genetika metabolismus MeSH
- pyridiny chemie MeSH
- racionální návrh léčiv MeSH
- receptory muskarinové chemie genetika metabolismus MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Stárnutí je neúprosný děj v životě každého organizmu a není tomu jinak ani v lidské říši. Podle světových statistik a demografických údajů se stále větší skupina naší populace dožívá vyššího věku. Článek se zabývá farmakologickou léčbou hyperaktivního močového měchýře (OverActive Bladder - OAB) u starších žen včetně zohlednění častých komorbidit ve vyšším věku. Prevalence OAB v tomto úseku života je vyšší než u ostatních, pro život závažnějších onemocnění. Pro geriatrické pacienty je méně klinických studií než pro pacienty v nižších věkových kategoriích. Efekt farmakologické léčby antimuskariniky proti placebu je prokazatelný ve všech věkových skupinách včetně osob starších 75 let. Vzhledem k polyfarmakoterapii u starších osob mohou antimuskarinika vstupovat do lékových interakcí. Proto v článku autoři na tato rizika upozorňují a doporučují, jak jim předcházet.
Aging is an inevitable process in the life of each organism and it is no different in the human world. According to the world statistics and demographic data, an ever increasing group in our population live to a ripe old age. The paper deals with pharmacological therapy for overactive bladder (OAB) in older women while also considering frequent comorbidities in older age. The prevalence of OAB at this life stage is greater as compared to other, more serious diseases. There are less clinical studies on geriatric patients than those focusing on younger age categories. The effect of pharmacotherapy with antimuscarinics against placebo is demonstrable within all age groups including people aged over 75. With regard to polypharmacotherapy in older adults, antimuscarinics may intervene in drug interactions. Therefore the authors draw attention to these risk factors and the ways to prevent them.
- Klíčová slova
- fesoterodin,
- MeSH
- agonisté beta-3-adrenergních receptorů klasifikace terapeutické užití MeSH
- antagonisté muskarinových receptorů * klasifikace metabolismus terapeutické užití MeSH
- benzhydrylové sloučeniny terapeutické užití MeSH
- farmakokinetika MeSH
- hyperaktivní močový měchýř * diagnóza farmakoterapie komplikace terapie MeSH
- inkontinence moči MeSH
- lékové interakce MeSH
- lidé MeSH
- močové ústrojí patofyziologie MeSH
- močový měchýř patofyziologie patologie MeSH
- senioři MeSH
- směrnice pro lékařskou praxi jako téma MeSH
- stárnutí * MeSH
- urologické látky farmakologie klasifikace terapeutické užití MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND AND PURPOSE: Conventional determination of agonist efficacy at G-protein coupled receptors is measured by stimulation of guanosine-5'-γ-thiotriphosphate (GTPγS) binding. We analysed the role of guanosine diphosphate (GDP) in the process of activation of the M₂ muscarinic acetylcholine receptor and provide evidence that negative cooperativity between agonist and GDP binding is an alternative measure of agonist efficacy. EXPERIMENTAL APPROACH: Filtration and scintillation proximity assays measured equilibrium binding as well as binding kinetics of [³⁵S]GTPγS and [³H]GDP to a mixture of G-proteins as well as individual classes of G-proteins upon binding of structurally different agonists to the M₂ muscarinic acetylcholine receptor. KEY RESULTS: Agonists displayed biphasic competition curves with the antagonist [³H]-N-methylscopolamine. GTPγS (1 µM) changed the competition curves to monophasic with low affinity and 50 µM GDP produced a similar effect. Depletion of membrane-bound GDP increased the proportion of agonist high-affinity sites. Carbachol accelerated the dissociation of [³H]GDP from membranes. The inverse agonist N-methylscopolamine slowed GDP dissociation and GTPγS binding without changing affinity for GDP. Carbachol affected both GDP association with and dissociation from G(i/o) G-proteins but only its dissociation from G(s/olf) G-proteins. CONCLUSIONS AND IMPLICATIONS: These findings suggest the existence of a low-affinity agonist-receptor conformation complexed with GDP-liganded G-protein. Also the negative cooperativity between GDP and agonist binding at the receptor/G-protein complex determines agonist efficacy. GDP binding reveals differences in action of agonists versus inverse agonists as well as differences in activation of G(i/o) versus G(s/olf) G-proteins that are not identified by conventional GTPγS binding.
- MeSH
- agonisté muskarinových receptorů metabolismus MeSH
- alosterická regulace MeSH
- antagonisté muskarinových receptorů metabolismus MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- guanosin 5'-O-(3-thiotrifosfát) metabolismus MeSH
- guanosindifosfát metabolismus MeSH
- kinetika MeSH
- křečci praví MeSH
- lidé MeSH
- N-methylskopolamin metabolismus MeSH
- proteiny vázající GTP klasifikace metabolismus MeSH
- radioligandová zkouška MeSH
- receptor muskarinový M2 genetika metabolismus MeSH
- rekombinantní proteiny genetika metabolismus MeSH
- transfekce MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- MeSH
- alkuronium farmakologie MeSH
- alosterická regulace MeSH
- antagonisté muskarinových receptorů farmakologie metabolismus MeSH
- atropin metabolismus MeSH
- benziláty metabolismus MeSH
- krysa rodu rattus MeSH
- myokard metabolismus MeSH
- receptory muskarinové metabolismus účinky léků MeSH
- techniky in vitro MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
