[H-3]dexmedetomidine, an alpha(2)-adrenoceptor agonist, detects a novel imidazole binding site in adult rat spinal cord

Binding properties of [H-3]dexmedetomidine [(+)-(S)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole] as an agonist-type radioligand for alpha(2)-adrenoceptors were characterised for the first time in tissues relevant to its analgesic (spinal cord from neonatal or adult rats) and behavioural (rat cerebral cortex) actions. In membranes of rat cerebral cortex (K(d)High 0.2 +/- 0.03 nM, K(d)Low 8.8 +/- 1.4 nM with B(max)High 130 +/- 11 fmol/mg protein, K(d)High 16%) and neonatal cord (K(d)High 0.3 +/- 0.04 nM, K(d)Low 14 +/- 3.7 nM with B(max)High 290 +/- 40 fmol/mg protein, R(High) 25%) Gpp(NH)p modifies the biphasic binding to monophasic and binding is competed with specifically by alpha(2)-adrenoceptor compounds. Binding to rat cerebral cortex is not modified by pretreatment with the noradrenergic neurotoxin, DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine). In contrast, [H-3]dexmedetomidine binding to adult rat spinal cord membranes is more complex and both saturation analysis and competition experiments indicate the presence of a non-adrenergic component of binding (about 40% of total binding) which is sensitive to imidazole-type compounds. This non-adrenergic component of [H-3]dexmedetomidine binding can be defined as a novel type of imidazole binding site such that, of the imidazoline I-1 or I-2 receptor ligands, only cimetidine has relatively high affinity. In conclusion, [H-3]dexmedetomidine shows very complex binding characteristics that limit its use as an agonist-type radioligand for alpha(2)-adrenoceptors but it may be a useful tool for imidazoline receptor characterisation.