Thiol group may be involved in the irreversible blockade of presynaptic α2-adrenoreceptors by pyrextramine and benextramine in the isolated guinea pig ileum

Brasili, Livio; Cassinelli, Anna; Angeli, Piero; Melchiorre, Carlo

doi:10.1016/0024-3205(86)90407-8

Cited by 4 publications

(3 citation statements)

References 12 publications

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“…This complies with data suggesting distinct basic residues of the ␣ 2A -AR that mediate G i and G s activation, respectively (Wade et al, 1999). Also, whereas classical irreversible antagonists such as the haloalkylamines are believed to form uncomplicated covalent bonds with the receptor, it has been proposed that benextramine inactivates receptors at distinct sites via a disulfide-thiol interchange reaction (Melchiorre et al, 1979;Brasili et al, 1980Brasili et al, , 1986Melchiorre, 1981;Melchiorre and Gallucci, 1983;Giardinà et al, 1996), thereby affecting the stereochemical properties of cysteine amino acid residues and probably disrupting the coupling of the ␣ 2A -AR to G i more than to G s .…”

Section: Discussionsupporting

confidence: 82%

Phenoxybenzamine and Benextramine, but Not 4-Diphenylacetoxy-N-[2-chloroethyl]piperidine Hydrochloride, Display Irreversible Noncompetitive Antagonism at G Protein-Coupled Receptors

Bodenstein¹,

Venter²,

Brink³

2005

J Pharmacol Exp Ther

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Many irreversible antagonists have been shown to inactivate G protein-coupled receptors (GPCRs) and used to study agonists and spare receptors. Presumably, they bind to primary (agonist) binding sites on the GPCR, although noncompetitive mechanisms of antagonism have been demonstrated but not thoroughly investigated. We studied noncompetitive antagonism by phenoxybenzamine and benextramine at ␣ 2A -adrenoceptors in stably transfected Chinese hamster ovary cells, benextramine and 4-diphenylacetoxy-N-[2-chloroethyl]piperidine hydrochloride (4-DAMP mustard) at endogenous muscarinic acetylcholine (mACh) receptors in human neuroblastoma SH-SY5Y cells, and benextramine at serotonin 5-HT 2A

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Section: Discussionsupporting

confidence: 82%

Phenoxybenzamine and Benextramine, but Not 4-Diphenylacetoxy-N-[2-chloroethyl]piperidine Hydrochloride, Display Irreversible Noncompetitive Antagonism at G Protein-Coupled Receptors

Bodenstein¹,

Venter²,

Brink³

2005

J Pharmacol Exp Ther

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“…The [3H]IDA binding site is more sensitive to alkylations by N-ethylmaleimide, and suggests a greater involvement of-SH groups in the control of the affinity of the alpha-2 adrenoceptor site. It has recently been reported that the irreversible blockade of presynaptic alpha-2 adrenoceptors by pyrextramine and benextramine in the isolated guinea pig ileum involves a thiol group (Brasili et al, 1986). Such particular features of some of the central and peripheral nervous system alpha-2 adrenoceptors explain the greater potency and selectivity of the tetramine disulfides to compete with [3H]IDA rather than with [3H]PRZ.…”

Section: Discussionmentioning

confidence: 98%

“…The ratios of the K~ values could be then used to draw a clear pharmacological differentiation between alpha-1 and alpha-2 sites. Finally, two alphaadrenergic antagonists (Brasili et aL, 1984(Brasili et aL, , 1986) that act on thiol groups (i.e. : pyrextramine and benextramine) were compared in their potencies to compete with the two radioligands.…”

Section: Introductionmentioning

confidence: 99%

Alpha-1 and alpha-2 adrenoceptor binding in cerebral cortex: Competition studies with [3H]prazosin and [3H]idazoxan

Reader

Brière

Grondin

1987

J. Neural Transmission

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The tritiated adrenergic antagonists prazosin ([3H]PRZ) and idazoxan ([3H]IDA, or RX-781094) bind specifically and with high affinity in membrane preparations from cerebral cortex to alpha-1- and alpha-2-adrenoceptors respectively. Saturation experiments, performed to determine the density of receptors (Bmax; maximum binding capacity) and the dissociation constant (Kd 25 degrees C), were analyzed by the methods of Eadie and Hofstee, iterative modelling, and the procedure of Hill. The pharmacologic properties and specificity of the labelling was verified by displacement experiments using alpha-adrenergic antagonists and agonists. The antagonist drugs showed the following order of potency to displace [3H]prazosin: prazosin much greater than phentolamine much greater than corynanthine greater than pyrextramine much greater than yohimbine much greater than piperoxan greater than benextramine greater than idazoxan; for the agonists: clonidine much greater than (-)-noradrenaline much greater than (-)-adrenaline much greater than phenylephrine, while other drugs, such as (-)-propranolol, dopamine, (-)-isoproterenol and serotonin only competed with the alpha-1-ligand at concentrations above 20 microM. The alpha 2-sites labelled by [3H]idazoxan were characterized by the antagonist displacement sequence idazoxan much greater than phentolamine greater than yohimbine = greater than piperoxan much greater than pyrextramine much greater than benextramine much greater than prazosin much greater than corynanthine. The agonists order of potency to compete with [3H]idazoxan was clonidine much greater than phenylephrine = greater than (-)-adrenaline greater than (-)-noradrenaline, and for other related drugs it was (-)-propranolol much greater than dopamine much greater than serotonin greater than (-)-isoproterenol. These competition experiments clearly showed two pharmacologically distinct sites, but question the relative specificity of some of the adrenergic drugs.

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Benextramine-neuropeptide Y (NPY) binding site interactions: Characterization of 3H-NPY binding site heterogeneity in rat brain

Doughty¹,

Li²,

Chu³

et al. 1992

Neuropeptides

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Thiol group may be involved in the irreversible blockade of presynaptic α2-adrenoreceptors by pyrextramine and benextramine in the isolated guinea pig ileum

Cited by 4 publications

References 12 publications

Phenoxybenzamine and Benextramine, but Not 4-Diphenylacetoxy-N-[2-chloroethyl]piperidine Hydrochloride, Display Irreversible Noncompetitive Antagonism at G Protein-Coupled Receptors

Phenoxybenzamine and Benextramine, but Not 4-Diphenylacetoxy-N-[2-chloroethyl]piperidine Hydrochloride, Display Irreversible Noncompetitive Antagonism at G Protein-Coupled Receptors

Alpha-1 and alpha-2 adrenoceptor binding in cerebral cortex: Competition studies with [3H]prazosin and [3H]idazoxan

Benextramine-neuropeptide Y (NPY) binding site interactions: Characterization of 3H-NPY binding site heterogeneity in rat brain

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