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RS‐45041‐190: a selective, high‐affinity ligand for I 2 imidazoline receptors

1995; Wiley; Volume: 116; Issue: 2 Linguagem: Inglês

10.1111/j.1476-5381.1995.tb16656.x

1476-5381

Christine M. Brown, Alison C. MacKinnon, William S. Redfern, A G Williams, C. Linton, Michael Stewart, R.U. Clague, Robin D. Clark, Michael Spedding,

Receptor Mechanisms and Signaling

RS‐45041‐190 (4‐chloro‐2‐(imidazolin‐2‐yl)isoindoUne) showed high affinity for I 2 imidazoline receptors labelled by [ 3 H]‐idazoxan in rat (p K i = 8.66 ±0.09), rabbit (p K i = 9.37 ± 0.07), dog (p K i = 9.32±0.18) and baboon kidney (p K i = 8.85 ±0.12), but had very low affinity for α 2 ‐adrenoceptors in rat cerebral cortex (p K i = 5.7 ± 0.09) RS‐45041‐190 showed low affinity for other adrenoceptors, dopamine, 5‐hydroxytryptamine, and muscarinic receptors and dihydropyridine binding sites (selectivity ratio > 1000) RS‐45041‐190 showed moderate potency for the inhibition of monoamine oxidase A in vitro (pIC 50 = 6.12), but had much lower potency for monoamine oxidase B (pIC 50 = 4.47), neither of which equated with its affinity for I 2 receptors RS‐45041‐190 (0.001 to 3 mg kg −1 , i.v. and 1 ng‐50 μ i.e.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 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 I 2 imidazoline receptors and its hyperphagic effect may suggest a role for I 2 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 I 2 receptors.