PHARMACOLOGICAL STUDIES WITH 2 NEW ERGOLINE DERIVATIVES, THE POTENTIAL ANTIPSYCHOTICS LEK-8829 AND LEK-8841

The pharmacological properties of 9,10-didehydro-N-methyl-N-(2-propyny l)-6-methyl-8 beta-am inomethylergoline (LEK-8829) and -didehydro-N-me thyl-N-(2-propynyl)-2-bromo-6-meth- ylergoline-8 beta-carboxamide (LEK -8841), new ergoline derivatives, were compared with those of haloperi dol and clozapine by in vitro radioligand displacement assays, various behavioral tests and blood pressure measurements. Both ergolines disp layed low affinity for rat striatal H-3-SCH23390 (7-chloro-8-hydroxy-3 -methyl-1 -phenyl-2, 3, 4, 5-tetrahydro-1H-3-benzazepine)-labeled dopa mine (D)(1) binding sites and high affinity for striatal H-3-spiperone -labeled D-2 and cortical H-3-ketanserin-labeled serotonin-2 (5-HT2) s ites. The ratio of pKi values 5-HT2/D-2 was 1.11 for LEK-8829 (close t o that of clozapine, 1.13) and 0.98 for LEK-8841 (close to that of hal operidol, 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 hal operidol, showed a certain degree of mesolimbic selectivity, i.e., the y caused more potent inhibition of apomorphine-induced locomotion comp ared with the induction of catalepsy in rats. In the case of LEK-8829, nonspecific effects that presumably predict a side effect profile, su ch as potentiation of pentobarbital-induced anesthesia in mice (sedati on), antagonism of oxotremorine-induced tremors in mice (anticholinerg ic activity), spontaneous locomotor activity in mice and norepinephrin e-induced lethality in rats (sedation and hypotension), were relativel y weak compared with the activities described earlier. In contrast, LE K-8841 showed nonspecific effects at the similar dose levels as dopami ne and 5-HT antagonistic effects. The results of direct measurements o f the influences of both compounds on blood pressure agreed with the p reviously mentioned findings, i.e., LEK-8829 was relatively less hypot ensive than LEK-8841 was. It is suggested that LEK-8829 might be an ef ficient antipsychotic with a reduced propensity to cause sedative, ant icholinergic and hypotensive side effects. A certain degree of mesolim bic selectivity also points toward the possibility of a reduced propen sity to cause extrapyramidal symptoms. In contrast, in regard to side effects (including extrapyramidal symptoms), the profile of LEK-8841 i s less promising.