CHARACTERISTICS OF THE BINDING OF THE ANTIHYPERTENSIVE AGENT MOXONIDINE TO ALPHA-2-ADRENOCEPTORS IN RAT-BRAIN MEMBRANES

  • 1 October 1988
    • journal article
    • research article
    • Vol. 38-2  (10) , 1442-1445
Abstract
The characteristics of the .alpha.2-adrenoceptor binding property of moxonidine (4-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-6-methoxy-2-methyl-5-pyrimidinamine, BDF 5895), a newly developed centrally acting antihypertensive agent, was investigated in receptor binding assays using [3H]-rauwolscine bound to rat cortex membranes. The results are as follows: 1. [3H]-Rauwolscine binds in a saturable manner to rat cerebral cortex membranes with a Bmax of 320 .+-. 50 fmol/mg of protein and KD of 1.7 .+-. 0.5 nmol/l. 2. The .alpha.2-adrenoceptor antagonist yohimbine competes with a Ki value of 8.0 nmol/l and slope factor close to unity. (-)-Norepinephrine competes with an overall Ki-value of 50 nmol/l and slope factor of 0.61. Mg2+ concentrations of 10 mmol/l in the presence of 0.1 mmol/l 3''-guanylimidodiphosphate (Gpp(NH)p) (Mg2+/Gpp(NH)p) do not affect the yohimbine inhibition curve, but increase the (-)-norepinephrine Ki value to 2.8 .mu.mol and the slope factor to unity. 3. Moxonidine competes with [3H]-rauwolscine binding with an overall Ki value of 460 nmol/l and slope factor of 0.72. Moxonidine binding inhibition was potentiated by Mg2+, but shifted to lower potency by Mg2+/Gpp(NH)p and 150 mmol/l NaCl. 4. Binding inhibition curves for (-)-norepinephrine and moxonidine fitted better to a 2-site model and could be interpreted in terms of high affinity site (with Ki value KH) and low affinity site (with Ki value KL). The effect of Mg2+/Gpp(NH)p and NaCl was to convert the high affinity sites to low affinity sites. 5. The Ki value of moxonidine to compete with [3H]-prozosin in cerebral cortex membranes is 36.5 .mu.mol/l. As KL for moxonidine is 3.7 .mu.mol/l, this means moxonidine is 10-fold selective for .alpha.2-adrenoceptors over .ALPHA.1-adrenoceptors.

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