RS-45041-190: a selective, high-affinity ligand for I2 imidazoline receptors.
1. RS-45041-190 (4-chloro-2-(imidazolin-2-yl)isoindoline) showed high affinity for I2 imidazoline receptors labelled by [3H]-idazoxan in rat (pKi = 8.66 +/- 0.09), rabbit (pKi = 9.37 +/- 0.07), dog (pKi = 9.32 +/- 0.18) and baboon kidney (pKi = 8.85 +/- 0.12), but had very low affinity for alpha 2-adrenoceptors in rat cerebral cortex (pKi = 5.7 +/- 0.09). 2. RS-45041-190 showed low affinity for other adrenoceptors, dopamine, 5-hydroxytryptamine, and muscarinic receptors and dihydropyridine binding sites (selectivity ratio > 1000). 3. RS-45041-190 showed moderate potency for the inhibition of monoamine oxidase A in vitro (pIC50 = 6.12), but had much lower potency for monoamine oxidase B (pIC50 = 4.47), neither of which equated with its affinity for I2 receptors. 4. RS-45041-190 (0.001 to 3 mg kg-1, i.v. and 1 ng-50 micrograms i.c.v.) had only small, transient effects on blood pressure and heart rate in anaesthetized rats. In conscious rats, RS-45041-190 had no effect on body core temperature or tail skin temperature (1 mg kg-1, s.c.) or on activity or rotarod performance (10 mg kg-1, i.p.). There were also no effects on barbiturate sleeping time in mice after doses of 1-10 mg kg-1, i.p. 5. RS-45041-190 (10 and 25 mg kg-1, i.p.) significantly increased food consumption in rats for up to 4 h after dosing, but unlike idazoxan (10 mg kg-1, i.p.) did not increase water consumption. RS-45041-190 is therefore a selective, high-affinity ligand at I2 imidazoline receptors and its hyperphagic effect may suggest a role for I2 imidazoline receptors in the modulation of appetite.However, in the absence of a selective agonist it is unclear whether this ligand is an agonist or an antagonist at I2 receptors.
Brown
C M
CM
Department of Pharmacology, Syntex Research Centre, Research Park, Riccarton, Edinburgh.
MacKinnon
A C
AC
Redfern
W S
WS
Williams
A
A
Linton
C
C
Stewart
M
M
Clague
R U
RU
Clark
R
R
Spedding
M
M
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001066:Appetite / Q000187:drug effects; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D004146:Dioxanes / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D019329:Idazoxan; D007093:Imidazoles / Q000494:pharmacology*; D054755:Imidazoline Receptors; D007668:Kidney / Q000187:drug effects*; D008297:Male; D051379:Mice; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000187:drug effects*; D013997:Time Factors
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D007093:Imidazoles; D054755:Imidazoline Receptors; D011955:Receptors, Drug; D019329:Idazoxan