The effects of brucine and alcuronium on the inhibition of [<sup>3</sup>H]acetylcholine release from rat striatum by muscarinic receptor agonists

Doležal, Vladimı́r; Tuček, Stanislav

doi:10.1038/sj.bjp.0701966

Cited by 42 publications

(27 citation statements)

References 28 publications

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“…In the first set of experiments, we investigated the effect of thiochrome on 50 mM potassium stimulation-evoked liberation of ACh from rat striatal cholinergic interneurones, which have been shown to possess inhibitory presynaptic M 4 muscarinic receptors (Dolezal and Tucek, 1998;Zhang et al, 2002). Depolarization with 50 mM potassium directly depolarizes nerve terminals and precludes the propagation of action potentials.…”

Section: Resultsmentioning

confidence: 99%

Thiochrome Enhances Acetylcholine Affinity at Muscarinic M4 Receptors: Receptor Subtype Selectivity via Cooperativity Rather than Affinity

Lazareno

Doležal²,

Popham³

et al. 2004

Molecular Pharmacology

100

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Thiochrome (2,7-dimethyl-5H-thiachromine-8-ethanol), an oxidation product and metabolite of thiamine, has little effect on the equilibrium binding of L-[ 3 3 H]ACh from potassium-stimulated slices of rat striatum, which contain autoinhibitory presynaptic M 4 receptors, but not from hippocampal slices, which contain presynaptic M 2 receptors. We conclude that thiochrome is a selective M 4 muscarinic receptor enhancer of ACh affinity and has neutral cooperativity with ACh at M 1 to M 3 receptors; it therefore demonstrates a powerful new form of selectivity, "absolute subtype selectivity", which is derived from cooperativity rather than from affinity.Most receptor-active ligands bind to the same site as the endogenous ligand, the so-called orthosteric site. Agonists mimic the actions of the endogenous ligand, whereas antagonists physically prevent the endogenous ligand from binding but lack its actions. The property of a ligand that determines its effect when bound to a receptor is called its efficacy. Different degrees of efficacy lead to so-called full agonists, partial agonists with a smaller maximal effect than full agonists; neutral antagonists, which occupy the active site without exerting any effect; and inverse agonists, which reduce the activity of constitutively active receptors (Kenakin, 2002). The selectivity of an orthosteric ligand for one receptor or receptor subtype is determined by its affinity for the receptor and its efficacy at that receptor. The difference in affinity between the target receptor and other receptors must be large for an orthosteric ligand to have useful selectivity. This can be difficult to achieve for receptors that show close homology at the orthosteric binding region such as the five subtypes of muscarinic receptor (M 1 -M 5 ) (Hulme et al., 1990). Selectivity derived from efficacy can also be hard to achieve, because the effect of a partial agonist depends on properties of the tissue, such as receptor density and downstream amplification mechanisms, which vary between cells and tissues, so a ligand with no apparent functional effect on tissues in vitro may nevertheless activate tissues in vivo, leading to unacceptable side effects (Terry et al., 2002).An alternative approach for developing selective ligands is to look for allosteric ligands that bind to a site on the receptor which is different from the site to which the endogenous ligand binds. This allows both types of ligand to bind simultaneously. If the affinity (or efficacy) of the endogenous ligand is different when it is bound to the allosteric liganded receptor compared with when it is bound to the free receptor, then the allosteric ligand exhibits positive or negative coop-

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Section: Resultsmentioning

confidence: 99%

Thiochrome Enhances Acetylcholine Affinity at Muscarinic M4 Receptors: Receptor Subtype Selectivity via Cooperativity Rather than Affinity

Lazareno

Doležal²,

Popham³

et al. 2004

Molecular Pharmacology

100

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“…The binding of a ligand at these allosteric sites induces a conformational change in the receptor, to either increase (positive cooperativity) or decrease (negative cooperativity) the binding of other ligands at the orthosteric site (Espinoza-Fonseca and Trujillo-Ferrara, 2005). For example, the binding of brucine to the allosteric site increases the affinity of the natural ligand aceylcholine by 2-fold at the orthosteric site of M1 receptor (Dolezal and Tucek, 1998). This is potentially useful in conditions such as Alzheimer's disease where the release of acetylcholine is reduced (Wess, 2005).…”

Section: Introductionmentioning

confidence: 98%

Muscarinic receptor binding activity of polyoxygenated flavones from Melicope subunifoliolata

Chung¹,

Yap²,

Goh³

et al. 2008

Phytochemistry

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“…To approach this question, we performed ex vivo experiments with rat brain cortical and striatal tissue. We investigated delayed wash-resistant effects of xanomeline on the regulation of stimulation-evoked release of acetylcholine (ACh) that is mediated by M 2 receptors in brain cortex and M 4 receptors in striatum (Doležal and Tuček, 1998;Zhang et al, 2002;Bymaster et al, 2003). We show that wash-resistant xanomeline binding decreases evoked ACh release by stimulating both M 2 and M 4 receptors and that both the allosteric and orthosteric binding sites participate in this effect.…”

mentioning

confidence: 99%

Wash-Resistantly Bound Xanomeline Inhibits Acetylcholine Release by Persistent Activation of Presynaptic M2 and M4 Muscarinic Receptors in Rat Brain

Machová¹,

Jakubík²,

El‐Fakahany³

et al. 2007

The Journal of Pharmacology and Experimental Therapeutics

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We studied the effects of 3-[3-hexyloxy-1,2,5-thiadiazo-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine (xanomeline) wash-resistant binding on presynaptic muscarinic regulation of electrically evoked [3 H]acetylcholine (ACh) release from rat brain slices. In both cortical and striatal tissues that possess M 2 and M 4 autoreceptors, respectively, immediate application of 10 M xanomeline had no effect on evoked [3 H]ACh release or its inhibition by 10 M carbachol. In contrast, preincubation with 1, 10, or 100 M xanomeline for 15 min decreased evoked release of ACh measured after 53 min of washing in xanomeline-free medium in a concentration-dependent manner. The maximal inhibitory effect equaled the immediate effect of the muscarinic full agonist carbachol, and it was completely (at 1 and 10

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The effects of brucine and alcuronium on the inhibition of [³H]acetylcholine release from rat striatum by muscarinic receptor agonists

Cited by 42 publications

References 28 publications

Thiochrome Enhances Acetylcholine Affinity at Muscarinic M4 Receptors: Receptor Subtype Selectivity via Cooperativity Rather than Affinity

Thiochrome Enhances Acetylcholine Affinity at Muscarinic M4 Receptors: Receptor Subtype Selectivity via Cooperativity Rather than Affinity

Muscarinic receptor binding activity of polyoxygenated flavones from Melicope subunifoliolata

Wash-Resistantly Bound Xanomeline Inhibits Acetylcholine Release by Persistent Activation of Presynaptic M2 and M4 Muscarinic Receptors in Rat Brain

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The effects of brucine and alcuronium on the inhibition of [3H]acetylcholine release from rat striatum by muscarinic receptor agonists

Cited by 42 publications

References 28 publications

Thiochrome Enhances Acetylcholine Affinity at Muscarinic M4 Receptors: Receptor Subtype Selectivity via Cooperativity Rather than Affinity

Thiochrome Enhances Acetylcholine Affinity at Muscarinic M4 Receptors: Receptor Subtype Selectivity via Cooperativity Rather than Affinity

Muscarinic receptor binding activity of polyoxygenated flavones from Melicope subunifoliolata

Wash-Resistantly Bound Xanomeline Inhibits Acetylcholine Release by Persistent Activation of Presynaptic M2 and M4 Muscarinic Receptors in Rat Brain

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The effects of brucine and alcuronium on the inhibition of [³H]acetylcholine release from rat striatum by muscarinic receptor agonists