DISCRIMINATION AND PHARMACOLOGICAL CHARACTERIZATION OF I-2-IMIDAZOLINE SITES WITH [H-3] IDAZOXAN AND ALPHA-2 ADRENOCEPTORS WITH [H-3] RX821002 (2-METHOXY IDAZOXAN) IN THE HUMAN AND RAT BRAINS

The alpha-2 adrenoceptor antagonist idazoxan has been shown to also recognize with high affinity nonadrenoceptor sites (12-imidazoline sites). In contrast, the 2-methoxy derivative of idazoxan, 2-methoxy idazoxan (RX821002), binds almost exclusively to alpha-2 adrenoceptors. The purpose of this study was to assess and extend the pharmacological characterization of 12-imidazoline sites and alpha-2 adrenoceptors in the human and rat brains. Competition studies with several imidazoli(di)ne/guanidine drugs and other nonrelated structures were performed in cortical membranes against [H-3]idazoxan (4 nM in the presence of 1 0(-6) M /-epinephrine to prevent binding to alpha-2 adrenoceptors) or [H-3]RX821002 (1 nM). Drugs such as cirazoline, guanoxan, naphazoline, tolazoline, clonidine, bromoxidine (UK 14,304) and phenylbiguanide displaced [H-3]idazoxan from two distinct binding sites, which suggested the existence of two affinity states for 12-imidazoline sites that were not modulated by MgCl2 or the nucleotide analog guanylyl-5'-imido-diphosphate. Binding affinities at the low-affinity site (K(iL)) were consistently more than 2 orders of magnitude lower than binding affinities at the high-affinity site (K(IH)), and there was a good correlation between K(IH) and K(IL) values for a given drug in the human (r = 0.89) and rat (r = 0.92) brains. For 18 to 22 drugs, the K(i) values in the human brain correlated well with the corresponding K(i) values in the rat brain both for I2-iMidazoline sites (r = 0.94) and alpha-2 adrenoceptors (r = 0.97). However, the K(i) values for 12-imidazoline sites did not correlate with the K values for alpha-2 adrenoceptors in human and rat brains. The order of drug potency for the 12-imidazoline sites was: guanoxan (1.3 nM) almost-equal-to cirazoline > idazoxan almost-equal-to naphazoline > clonidine > phentolamine > RX821002 > (8aR, 12aS, 13aS)-3-methoxy-12-methanesulfonyl-5,6,8a,9, 10,11,12,12a,13,13a-decahydro-8H-isoquino[2,1-g]-naphthyridine (RS 15385-197) (>l 0 muM). In contrast, the potencies at the alpha-2 adrenoceptor were: RS 1538-197 (0.3 nM) > RX821002 > clonidine > phentolamine > idazoxan almost-equal-to naphazoline > guanoxan almost-equal-to cirazoline (307 nM). The results demonstrate that I2-imidazoline sites (labeled by [H-3]idazoxan) and alpha-2 adrenoceptors are different pharmacological entities with similar characteristics in the human and rat brains. In both species, I2-imidazoline sites are markedly heterogeneous in nature.