Characteristics of the binding of the antihypertensive agent moxonidine to alpha 2-adrenoceptors in rat brain membranes.
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-pyrim idinamine, 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 mumol 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Ferry
D
D
Department of Biochemical Pharmacology, University of Innsbruck, Austria.
Armah
B I
BI
Goll
A
A
Glossmann
H
H
D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism*; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D005260:Female; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D007093:Imidazoles / Q000378:metabolism*; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism*; D015016:Yohimbine / Q000378:metabolism
D000959:Antihypertensive Agents; D007093:Imidazoles; D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine; D006165:Guanylyl Imidodiphosphate; C043482:moxonidine; D008274:Magnesium; D009638:Norepinephrine