RS‐45041‐190: a selective, high‐affinity ligand for I₂ imidazoline receptors

Abstract

1 RS-45041-190 (4-chloro-2-(imidazolin-2-yl)isoindoline) showed high affinity for 12 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 a2-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 (pICs = 4.47), neither of which equated with its affinity for I2 receptors. 4 RS-45041-190 (0.001 to 3 mg kg-', i.v. and 1 ng-50 yg 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-', 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-, i.p.5 RS-45041-190 (10 and 25 mg kg-', i.p.) significantly increased food consumption in rats for up to 4 h after dosing, but unlike idazoxan (10 mg kg-, i.p.) did not increase water consumption. 6 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.

Role of intracellular Ca2+ signaling in the antinociceptive and discriminative stimulus effects of the imidazoline I2 receptor agonist 2-BFI in rats

“…The I 2 receptor ligand BU224 fully substituted for 2-BFI, which is consistent with previous reports (MacInnes and Handley 2002). RS45041, CR4056 and tracizoline, which bind to I 2 receptors with high selectivity over many other receptors including α 2 adrenoceptors and imidazoline I 1 receptors (Brown et al 1995; Ferrari et al 2011; Pigini et al 1997) also all fully substituted for 5.6 mg/kg 2-BFI. In rats discriminating 10 mg/kg CR4056 from its vehicle, 2-BFI produced a maximum of 75% CR4056-associated lever responding (Qiu et al 2014).…”

“…Control 2-BFI dose-effect curves were periodically established throughout the study to ensure the performance stability of 2-BFI discrimination. In substitution studies, compounds with known I 2 R activity (BU224, 4-chloro-2-(imidazolin-2-yl)isoindoline (RS45041), CR4056, tracizoline, S22687, phenyzoline and idazoxan) (Brown et al 1995; Ferrari et al 2011; Pigini et al 1997; Qiu et al 2015) were tested to examine the generality of the discriminative stimulus effects of 2-BFI. A serotonin 5-HT 2A receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) was tested as a negative control to examine the pharmacological specificity of 2-BFI discriminative stimulus.…”

Discriminative stimulus effects of the imidazoline I2 receptor ligands BU224 and phenyzoline in rats

“…Nonetheless, medicinal chemistry efforts have led to a number of highly selective I 2 receptor ligands, including those tested in this study (Thorn et al, 2012). For example, RS45041 is a highly selective I 2 receptor ligand with high affinity for I 2 receptors and very low affinity (> 1000-fold) for adrenoceptors, dopamine, 5-HT, muscarinic receptors and dihydropyridine binding sites (Brown et al, 1995). Tracizoline is a cirazoline analog with high affinity and selectivity for I 2 receptors over α 2 adrenoceptors (7431-fold) and less selective for I 1 receptors (10-fold) (Pigini et al, 1997).…”

Characterization of the hypothermic effects of imidazoline I2 receptor agonists in rats

“…However, the understanding of I 2 receptors has long been hampered by the lack of valid functional assays and selective ligands. Over the years, several selective I 2 receptor ligands have been developed such as RS‐45041‐190, 2‐BFI, BU224, tracizoline and LSL60101 (Alemany et al ., 1995; Brown et al ., 1995; Hudson et al ., 2003; Gentili et al ., 2006). These compounds have been valuable research tools to facilitate the better understanding of I 2 receptors.…”