Author/Editor     Krisch, I; Bole-Vunduk, B; Lavrič, B; Ocvirk, A; Pepelnak, M; Budihna, MV; Sket, D
Title     Pharmacological studies with two new ergoline derivatives, the potential antipsychotics LEK-8829 and LEK-8841
Type     članek
Source     J Pharmacol Exp Ther
Vol. and No.     Letnik 271, št. 1
Publication year     1994
Volume     str. 343-52
Language     eng
Abstract     The pharmacological properties of 9,10-didehydro-N-methyl-N-(2-propynyl)-6-methyl-8 beta-aminomethylergoline (LEK-8829) and 9,10-didehydro-_N-methyl-N-(2-propynyl)-2-bromo-6-methylergoline-8B-carboxamide (LEK-8841), new ergoline derivatives, were compared with those of haloperidol and clozapine by in vitro radioligand displacement assays, various behavioral tests and blood pressure measurements. Both ergolines displayed low affinity for rat striatal 3H-SCH23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine)-labeled dopamine (D)1 binding sites and high affinity for striatal 3H-spiperone-labeled D2 and cortical 3H-ketanserin-labeled serotonin-2 (5-HT2) sites. The ratio of pKi values 5-HT2/D2 was 1.11 for LEK-8829 (close to that of clozapine, 1.13) and 0.98 for LEK-8841 (close to that of haloperidol, 0.95). All compounds inhibited apomorphine-induced locomotor activity in rats, apomorphine-induced climbing behavior in mice and 5-hydroxytryptophan-induced head twitches in mice and induced catalepsy in rats and in mice. LEK-8829 and clozapine, but not LEK-8841 and haloperidol, showed a certain degree of mesolimbic selectivity, i.e., they caused more potent inhibition of apomorphine-induced locomotion compared with the induction of catalepsy in rats. In the case of LEK-8829, nonspecific effects that presumably predict a side effect profile, such as potentiation of pentobarbital-induced anesthesia in mice (sedation), antagonism of oxotremorine-induced tremors in mice (anticholinergic activity), spontaneous locomotor activity in mice and norepinephrine- induced lethality in rats (sedation and hypotension) were relatively weak compared with the activities described earlier. In contrast, LEK-8841 showed nonspecific effects at the similar dose levels as dopamine and 5-HT antagonistic effects. The results of direct measurements of the influences of both compounds on blood pressure agreed with the previously mentioned findings, i.e.(trunc.)
Descriptors     ERGOLOID MESYLATES
CATALEPSY
APOMORPHINE
NOREPINEPHRINE
BLOOD PRESSURE
ANIMALS, LABORATORY
RATS
MICE
RADIOLIGAND ASSAY
PENTOBARBITAL
BEHAVIOR, ANIMAL
OXOTREMORINE
LOCOMOTION
SEROTONIN
CLOZAPINE