Ligand Efficacy and Potency at Recombinant α2 Adrenergic Receptors

Jasper, Jeffrey R.; Lesnick, John; Chang, Leon; Yamanishi, Susan S; Chang, Thomas K. H.; Hsu, Sherry; Daunt, David A.; Bonhaus, Douglas W.; Eglen, Richard M.

doi:10.1016/s0006-2952(97)00631-x

Cited by 142 publications

(120 citation statements)

References 21 publications

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“…These ligands revealed the following rank order of high-magnitude Ca 2+ response [E max (%) versus 10 mM (7)-adrenaline]: UK 14304 (102+4)=ta-lipexole (101+3)=(7)-adrenaline (100)=d-medetomidine (98+1)4oxymetazoline (81+4)^clonidine (75+5). This rank order of agonists is similar to that obtained earlier by measuring [ 35 S]-GTPgS binding, Ca 2+ and GTPase responses in CHO and HEK 293 cells stably transfected with a wt a 2C AR (Jasper et al, 1998;Kukkonen et al, 1998;Jansson et al, 1999). Co-exposure of cells to (7)-adrenaline with the putative antagonist RX 811059 displayed competitive antagonism of the (7)-adrenaline-mediated high-magnitude Ca 2+ response with a pA 2 value of 7.57+0.14 ( Figure 3).…”

Section: Resultssupporting

confidence: 87%

Partial to complete antagonism by putative antagonists at the wild‐type α_2C‐adrenoceptor based on kinetic analyses of agonist : antagonist interactions

Pauwels

Colpaert

2000

British J Pharmacology

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1 Activation of the recombinant human a 2C -adrenoceptor (a 2C AR) by (7)-adrenaline in CHO-K1 cells transiently co-expressing a chimeric G aq/i1 protein induced a rapid, transient Ca 2+ response with a high-magnitude followed by a low-magnitude phase which continued throughout the recorded time period (15 min). 2 Activation of the a 2C AR by various a 2 AR agonists revealed the following rank order of highmagnitude Ca 2+ response [E max (%) versus 10 mM (7)-adrenaline]: UK 14304 (102+4)=talipexole (101+3)=(7)-adrenaline (100)=d-medetomidine (98+1)4oxymetazoline (81+4)^clonidine (75+5). 3 The methoxy-(RX 821002) and ethoxy-derivatives (RX 811059) of idazoxan and the dexefaroxan analogue atipamezole were fully e ective as antagonists of both the high-and the low-magnitude Ca 2+ response. However, though acting as full antagonists of the high-magnitude response, the further putative a 2 AR antagonists idazoxan (27%), SKF 86466 (29%) and dexefaroxan (59%) reversed the low-magnitude response only partially. 4 In conclusion, kinetic analyses of agonist : antagonist interactions at the a 2C AR demonstrate a wide spectrum of partial to complete antagonism of the low-magnitude Ca 2+ response for structurally related a 2 AR ligands.

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Section: Resultssupporting

confidence: 87%

Partial to complete antagonism by putative antagonists at the wild‐type α_2C‐adrenoceptor based on kinetic analyses of agonist : antagonist interactions

Pauwels

Colpaert

2000

British J Pharmacology

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“…This catecholamine binds to ␣ 2 ARs with high affinity 13,21 but does not recognize I 1 BS at all. 13 It is a full agonist at human and murine ␣ 2A ARs.…”

Section: Discussionmentioning

confidence: 99%

“…13 It is a full agonist at human and murine ␣ 2A ARs. 21 Therefore, ␣-MNA can be considered a "pure" ␣ 2A AR agonist.…”

Section: Discussionmentioning

confidence: 99%

Evidence for Synergy Between α ₂ -Adrenergic and Nonadrenergic Mechanisms in Central Blood Pressure Regulation

Bruban¹,

Estato²,

Schann³

et al. 2002

Circulation

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Background-Both ␣ 2 -adrenergic and non-␣ 2 -adrenergic mechanisms seem to be involved in the hypotensive effect of imidazoline-like drugs. This study aimed at investigating how these 2 mechanisms work together to modify blood pressure (BP). Methods and Results-LNP 509, which appeared in this study to be devoid of ␣ 2A -adrenergic activity, was administered to anesthetized rabbits and wild-type (WT) mice into the cisterna magna and into the fourth ventricle, respectively. Mean arterial pressure decreased by a maximum of 46Ϯ4% and 16Ϯ2%, respectively. In D79N mice, which lack functional ␣ 2A -adrenergic receptors, LNP 509 also reduced mean arterial pressure by 17Ϯ2%. The hypotension induced by LNP 509 (100 g/kg intracisternally) was prevented by S23757 (1 mg/kg intracisternally), an antagonist highly selective for I 1 -imidazoline binding sites (I 1 BS). A synergy between LNP 509 and the ␣ 2 -adrenergic agonist ␣-methylnoradrenaline (␣-MNA) was observed in rabbits (cisterna magna injection) and in WT mice (fourth ventricle injection) but not, as expected, in D79N mice. Similar to LNP 509 alone, rilmenidine (fourth ventricle injection), which binds both to ␣ 2 -adrenergic receptors and to I 1 BS, decreased BP in D79N mice. In WT animals, rilmenidine had a significantly greater effect. Microinjections performed in rabbits showed that the synergism occurred at least in part in the nucleus reticularis lateralis of the brain stem. Conclusions-These results demonstrate that a central imidazoline-sensitive, but non-␣ 2 -adrenergic, mechanism can modify BP by itself. This mechanism, which may involve I 1 BS, interacts synergistically with an ␣ 2 -adrenergic mechanism to decrease BP.

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“…To study the effects of the ␣ 1 receptor in isolation, we next blocked the ␣ 2 receptors with the selective ␣ 2 receptor antagonist RX821002 (0.3-0.5 M) (Jasper et al 1998;Sanders et al 2006) prior to applying the agonist A61603. This effectively made A61603 highly selective for the ␣ 1A adrenergic receptor (Craig et al 1997).…”

Section: Llrs Are Increased By ␣ 1a Receptorsmentioning

confidence: 99%

Adrenergic Receptors Modulate Motoneuron Excitability, Sensory Synaptic Transmission and Muscle Spasms After Chronic Spinal Cord Injury

Rank

Murray

Stephens

et al. 2011

Journal of Neurophysiology

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Rank MM, Murray KC, Stephens MJ, D'Amico J, Gorassini MA, Bennett DJ. Adrenergic receptors modulate motoneuron excitability, sensory synaptic transmission and muscle spasms after chronic spinal cord injury. J Neurophysiol 105: 410 -422, 2011. First published November 3, 2010 doi:10.1152/jn.00775.2010. The brain stem provides most of the noradrenaline (NA) present in the spinal cord, which functions to both increase spinal motoneuron excitability and inhibit sensory afferent transmission to motoneurons (excitatory postsynaptic potentials; EPSPs). NA increases motoneuron excitability by facilitating calcium-mediated persistent inward currents (Ca PICs) that are crucial for sustained motoneuron firing. Spinal cord transection eliminates most NA and accordingly causes an immediate loss of PICs and emergence of exaggerated EPSPs. However, with time PICs recover, and thus the exaggerated EPSPs can then readily trigger these PICs, which in turn produce muscle spasms. Here we examined the contribution of adrenergic receptors to spasms in chronic spinal rats. Selective activation of the ␣ 1A adrenergic receptor with the agonists methoxamine or A61603 facilitated Ca PIC and spasm activity, recorded both in vivo and in vitro. In contrast, the ␣ 2 receptor agonists clonidine and UK14303 did not facilitate Ca PICs, but did decrease the EPSPs that trigger spasms. Moreover, in the absence of agonists, spasms recorded in vivo were inhibited by the ␣ 1 receptor antagonists WB4010, prazosin, and REC15/2739, and increased by the ␣ 2 receptor antagonist RX821001, suggesting that both adrenergic receptors were endogenously active. In contrast, spasm activity recorded in the isolated in vitro cord was inhibited only by the ␣ 1 antagonists that block constitutive receptor activity (activity in the absence of NA; inverse agonists, WB4010 and prazosin) and not by the neutral antagonist REC15/2739, which only blocks conventional NA-mediated receptor activity. RX821001 had no effect in vitro even though it is an ␣ 2 receptor inverse agonist. Our results suggest that after chronic spinal cord injury Ca PICs and spasms are facilitated, in part, by constitutive activity in ␣ 1 adrenergic receptors. Additionally, peripherally derived NA (or similar ligand) activates both ␣ 1 and ␣ 2 adrenergic receptors, controlling PICs and EPSPs, respectively.

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Ligand Efficacy and Potency at Recombinant α2 Adrenergic Receptors

Cited by 142 publications

References 21 publications

Partial to complete antagonism by putative antagonists at the wild‐type α_2C‐adrenoceptor based on kinetic analyses of agonist : antagonist interactions

Partial to complete antagonism by putative antagonists at the wild‐type α_2C‐adrenoceptor based on kinetic analyses of agonist : antagonist interactions

Evidence for Synergy Between α ₂ -Adrenergic and Nonadrenergic Mechanisms in Central Blood Pressure Regulation

Adrenergic Receptors Modulate Motoneuron Excitability, Sensory Synaptic Transmission and Muscle Spasms After Chronic Spinal Cord Injury

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Ligand Efficacy and Potency at Recombinant α2 Adrenergic Receptors

Cited by 142 publications

References 21 publications

Partial to complete antagonism by putative antagonists at the wild‐type α2C‐adrenoceptor based on kinetic analyses of agonist : antagonist interactions

Partial to complete antagonism by putative antagonists at the wild‐type α2C‐adrenoceptor based on kinetic analyses of agonist : antagonist interactions

Evidence for Synergy Between α 2 -Adrenergic and Nonadrenergic Mechanisms in Central Blood Pressure Regulation

Adrenergic Receptors Modulate Motoneuron Excitability, Sensory Synaptic Transmission and Muscle Spasms After Chronic Spinal Cord Injury

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Partial to complete antagonism by putative antagonists at the wild‐type α_2C‐adrenoceptor based on kinetic analyses of agonist : antagonist interactions

Partial to complete antagonism by putative antagonists at the wild‐type α_2C‐adrenoceptor based on kinetic analyses of agonist : antagonist interactions

Evidence for Synergy Between α ₂ -Adrenergic and Nonadrenergic Mechanisms in Central Blood Pressure Regulation