FCE 23884, substrate-dependent interaction with the dopaminergic system. II. Preclinical biochemical studies.
The effects of FCE 23884 [4-(9,10-didehydro-6-methylergolin-8 beta-yl) methyl-piperazine-2,6-dione] were examined using a variety of biochemical methods. In vitro assays showed that FCE 23884 bound to D-2, alpha-2 and 5-hydroxytryptamine1A sites with Ki values of 6.5, 4.0 and 4.0 nM, respectively. The affinity for D-1 and S-2 receptors was moderate (submicromolar range) and slight or negligible for alpha-1, cholinergic and sigma receptors. In normal rats, FCE 23884 accelerated markedly dopamine (DA) turnover in the neostriatum and nucleus accumbens as indicated by the increased ratios of dihydroxphenyl acetic acid/DA and homovanillic acid/DA. The compound enhanced DA synthesis and utilization rate. After gamma-butyrolactone treatment, a model to study DA autoreceptors function, FCE 23884 almost antagonized completely the gamma-butyrolactone reversal induced by apomorphine on l-dihydroxyphenylalanine accumulation in the two brain areas. In addition, FCE 23884 induced a rapid 20-fold increase of serum prolactin confirming its DA antagonistic profile in normal rats. In contrast with these antidopaminergic properties, FCE 23884 consistently stimulated basal adenylate cyclase activity in vitro (ED50 = 0.6 microM) and elicited a rapid increase of cyclic AMP formation in the neostriatum of normal (35%) and reserpinized (82%) rats in vivo. Furthermore in this last condition both the DA turnover and synthesis rate in the neostriatum and nucleus accumbens decreased after treatment with FCE 23884. These neurochemical data support the behavioral studies indicating that FCE 23884 possesses mixed DA antagonist and agonist properties depending on the experimental conditions, the distinguishing factor being presence or absence of DA.(ABSTRACT TRUNCATED AT 250 WORDS)
Carfagna
N
N
R&D, Farmitalia Carlo Erba-Erbamont Group, Central Nervous System Department, Nerviano, MI, Italy.
Caccia
C
C
Mantegani
S
S
Cavanus
S
S
Fornaretto
M G
MG
Buonamici
M
M
Rossi
A C
AC
Roncucci
R
R
Fariello
R G
RG
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000378:metabolism / Q000494:pharmacology*; D018492:Dopamine Antagonists; D004873:Ergolines / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D012110:Reserpine / Q000494:pharmacology
D015259:Dopamine Agents; D018492:Dopamine Antagonists; D004873:Ergolines; D011954:Receptors, Dopamine; C071320:FCE 23884; D012110:Reserpine; D000262:Adenylyl Cyclases; D004298:Dopamine