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Br J Pharmacol. 2004 Oct;143(4):495-507. Epub 2004 Sep 27.

Allosteric modulation of semicarbazide-sensitive amine oxidase activities in vitro by imidazoline receptor ligands.

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1
Department of Pharmacology, 9-70 Medical Sciences Building, University of Alberta, Edmonton, Alberta, Canada T6G 2H7. Andy.Holt@ualberta.ca

Abstract

1. Evidence indicates that imidazoline I(2) binding sites (I(2)BSs) are present on monoamine oxidase (MAO) and on soluble (plasma) semicarbazide-sensitive amine oxidase enzymes. The binding site on MAO has been described as a modulatory site, although no effects on activity are thought to have been observed as a result of ligands binding to these sites. 2. We examined the effects in vitro of several imidazoline binding site ligands on activities of bovine plasma amine oxidase (BPAO) and porcine kidney diamine oxidase (PKDAO) in a spectrophotometric protocol. 3. While both enzymes were inhibited at high concentrations of all ligands, clonidine, cirazoline and oxymetazoline were seen, at lower concentrations, to increase activity of BPAO versus benzylamine, but not of PKDAO versus putrescine. This effect was substrate dependent, with mixed or biphasic inhibition of spermidine, methylamine, p-tyramine and beta-phenylethylamine oxidation observed at cirazoline concentrations that increased benzylamine oxidation. 4. With benzylamine as substrate, clonidine decreased K(M) (EC(50) 8.82 microm, E(max) 75.1% of control) and increased V(max) (EC(50) 164.6 microm, E(max) 154.1% of control). Cirazoline decreased V(max) (EC(50) 2.15 microm, E(max) 91.4% of control), then decreased K(M) (EC(50) 5.63 microm, E(max) 42.6% of control) and increased V(max) (EC(50) 49.0 microm, E(max) 114.4% of decreased V(max) value). 5. Data for clonidine fitted a mathematical model for two-site nonessential activation plus linear intersecting noncompetitive inhibition. Data for cirazoline were consistent with involvement of a fourth site. 6. These results reveal an ability of imidazoline ligands to modulate BPAO kinetics allosterically. The derived mechanism may have functional significance with respect to modulation of MAO by I(2)BS ligands.

PMID:
15451775
PMCID:
PMC1575421
DOI:
10.1038/sj.bjp.0705986
[Indexed for MEDLINE]
Free PMC Article
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