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In vivo effects of new inhibitors of catechol‐ O ‐methyl transferase
Author(s) -
Rivas Emilia,
De Ceballos Maria L,
Nieto Ofelia,
Fontenla José Angel
Publication year - 1999
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 - 10.1038/sj.bjp.0702474
Subject(s) - chemistry , in vivo , pharmacology , catechol o methyl transferase , reserpine , catalepsy , dopamine , stereochemistry , biochemistry , endocrinology , haloperidol , biology , microbiology and biotechnology , allele , gene
The effects of two new synthetic compounds showing in vitro catechol‐ O ‐methyl transferase (COMT) inhibitor properties were studied in vivo and compared with the effects of nitecapone and Ro‐41‐0960. QO IA (3‐(3‐hydroxy‐4‐methoxy‐5‐nitrobenzylidene)‐2,4‐pentanedione), QO IIR ([2‐(3,4‐dihydroxy‐2‐nitrophenyl)vinyl]phenyl ketone), nitecapone and Ro‐41‐0960 (30 mg kg −1 , i.p.) were given to reserpinized rats 1 h before the administration of L ‐DOPA/carbidopa (LD/CD, 50 : 50 mg kg −1 , i.p.). Locomotor activity was assessed 1 h later. All the COMT inhibitors (COMTI), with the exception of QO IA, markedly potentiated LD/CD reversal of reserpine‐induced akinesia. Similar results were obtained when the COMTI were coadministered with LD/CD. The effect of compound QO IIR was dose‐dependent (7.5–30 mg kg −1 , i.p.). The COMTI (30 mg kg −1 , i.p.) potentiated LD/CD reversal of both catalepsy and hypothermia of reserpinized mice. QO IIR, nitecapone and Ro‐41‐0960 (30 mg kg −1 , i.p.) reduced striatal 3‐methyl‐DOPA (3‐OMD) levels and increased dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels. Compound QO IA was devoid of any effect on striatal amine levels. In contrast to the other inhibitors, Ro‐41‐0961 reduced HVA levels as well. The effect of QO IIR on striatal amine levels was dose‐dependent (7.5–60 mg kg −1 , i.p.) These results suggest that the new compound QO IIR is an effective peripherally acting COMT inhibitor in vivo .British Journal of Pharmacology (1999) 126 , 1667–1673; doi: 10.1038/sj.bjp.0702474