Behavioral studies on LEK-8804, a new ergoline derivative with potent 5-HT1A receptor agonist and 5-HT2 receptor antagonist activity.

The 5-HT1A receptor-mediated tail flick response in rats and the 5-HT2 receptor-mediated head twitch response in mice were used to study the functional activity of a new ergoline derivative, 9,10-didehydro-N-(2-propynyl)-6-methylergoline-8 beta-carboxamide (LEK-8804). LEK-8804 dose-dependently elicited spontaneous tail flicks in rats, indicating a full 5-hydroxytryptamine1A (5-HT1A) agonist activity. This effect was very similar to that produced by the selective 5-HT1A agonist 8-OH-DPAT, both in terms of potency and time-effect relationship, and was blocked by the selective 5-HT1A antagonist NAN-190. In contrast, LEK-8804 by itself failed to produce head twitches in mice but dose-dependently inhibited the 5-hydroxytryptophan (5-HTP)-induced behavior. The inhibitory effect of LEK-8804 upon 5-HTP-induced head twitches was not attenuated by the selective 5-HT1A antagonist NAN-190. This indicates that probably not the agonist action on 5-HT1A receptors but instead the antagonism on 5-HT2 receptors was involved in the inhibition of head twitch response. It is suggested that LEK-8804 is a potent full 5-HT1A receptor agonist with possible 5-HT2 receptor antagonist properties.