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Different in vivo properties of three new inhibitors of catechol O ‐methyltransferase in the rat
Author(s) -
Männistö Pekka T.,
Tuomainen Päivi,
Tuominen Raimo K.
Publication year - 1992
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1992.tb09020.x
Subject(s) - pargyline , catechol o methyl transferase , homovanillic acid , monoamine oxidase , chemistry , endocrinology , medicine , carbidopa , striatum , monoamine oxidase inhibitor , in vivo , serotonin , dopamine , pharmacology , levodopa , biochemistry , biology , enzyme , genotype , receptor , microbiology and biotechnology , disease , parkinson's disease , gene
1 We compared three new catechol O ‐methyltransferase (COMT) inhibitors (OR‐611, Ro 40–7592 and CGP 28014; 10 and 30 mg kg −1 , i.p.) in male rats given levodopa ( l ‐DOPA, 50 mg kg −1 , i.p.) and carbidopa ((−)‐ l ‐α‐methyl dopa, 50 mg kg −1 , i.p.). In some studies pretreatment with pargyline (80 mg kg −1 , i.p.) was used to block the function of monoamine oxidase (MAO). 2 Decreases of hypothalamic and striatal 3‐ O ‐methyl‐dopa (3‐OMD) levels were used as measures of the inhibition of peripheral COMT. The inhibition of brain COMT activity was estimated by decreases of hypothalamic and striatal homovanillic acid (HVA) and 3‐methoxytyramine (3‐MT; after pargyline) levels. 3 The three COMT inhibitors studied had different individual characteristics. OR‐611 was primarily a peripherally acting COMT inhibitor, decreasing 3‐OMD levels in the striatum (to 31–52%) and in the hypothalamus (to 16–27%) both in the control and pargyline‐treated animals at 1 and 3 h. It did not have any effect on brain HVA and 3‐MT. 3 Ro 40–7592 was a broad spectrum COMT inhibitor decreasing striatal and hypothalamic 3‐OMD (always to < 30%), HVA (to < 50%) and 3‐MT levels (to < 23%) significantly both at 1 and 3 h. It was more potent than OR‐611. 4 CGP 28014 functioned as a weak COMT inhibitor in the periphery inhibiting 3‐OMD formation only at 3 h. In contrast, it was fairly potent in decreasing the brain HVA and 3‐MT levels at 1 h (to 37–22% and 42–35% in the striatum, and to 57–33% and 64–35% in the hypothalamus, respectively) but not at 3 h. Since CGP 28014, unlike OR‐611 and Ro 40–7592, did not generally increase the brain DOPA, dopamine or DOPAC levels, it was not a typical COMT inhibitor.