Lidanserin (ZK-33839)

Anxiolytics reverse the acceleration of ejaculation resulting from enforced intercopulatory intervals in rats

The enforced interval of copulation (EIC) consists of the artificial prolongation of the interintromission interval, induces a reduction in the number of intromissions preceding ejaculation, and is accompanied by an anxiety like behavioral repertoire. The administration of the benzodiazepine anxiolytics diazepam, chlordiazepoxide, flurazepam, and flunitrazepam produced a dose-dependent inhibition of the EIC effect with a concomitant increase in mounting. These actions were blocked by the central benzodiazepine antagonist Ro 15-1788. The anxiogenic agent beta-carboline Zk 39106 had no effect. Treatment with pentobarbital also produced a blockade of the reduction in the number of intromissions during EIC, whereas muscimol and bicuculline lacked this effect. The serotonergic anxiolytic buspirone reversed the facilitatory action induced by EIC; however, two putative serotonergic antianxiety agents, 8-OH-DPAT and ipsapirone, did not modify or potentiate it, respectively. Finally, the nonanxiolytic serotonergic compounds 5-hydroxytryptophan and TFMPP drastically increased the number of mounts but did not antagonize the reduction of intromissions produced by EIC. These results suggest that an increase in the anxiety levels may be responsible for the excitatory action of EIC on sexual behavior.

Pharmacological profile of a new potent 5-hydroxytryptamine (5-HT2) alpha 1-receptor antagonist

In in vitro binding studies ZK 33.839 (4-(3-[3-(4-(4-fluorobenzoyl)-1-piperidinyl)-propoxy]-4-methoxyphenyl)- 2-pyrrolidone) showed highly specific binding affinity for 5-hydroxytryptamine (5-HT2) and alpha 1-receptors. With 2.0 nmol/l and 5.2 nmol/l both Ki-values occur in the same concentration range. The pharmacodynamic profile of ZK 33.839 has been investigated under in vitro and in vivo conditions. In human platelets, in rat vascular smooth muscle and in guinea pig tracheal smooth muscle 5-HT-induced proaggregatory and contractile effects were inhibited dose-dependently with IC50-values ranging from 1.85 x 10(-8) mol/l to 9 x 10(-9) mol/l. 5-HT-induced amplification of the response of rabbit femoral artery to different vasoconstrictors (angiotensin II, histamine, norepinephrine, and prostaglandin F2 alpha) and 5-HT-mediated increase of microvascular permeability in hamster cheek pouch preparation were also inhibited by ZK 33.839. ZK 33.839 was found to be a potent alpha 1-receptor antagonist, the pA2-value in rat aortic strips determined against phenylephrine was 9.16. In blood-perfused hindquarters of anaesthetized rats, pretreated with reserpine, pressor dose-response curves to norepinephrine and 5-HT were shifted to a higher dose range. ZK 33.839 lowered blood pressure in conscious Dahl-S-rats and in anaesthetized rabbits. Decrease of blood pressure was due to a decrease of peripheral vascular resistance. Cardiac output and heart rate were not significantly altered. ZK 33.839 is a potential antihypertensive compound which combines vasodilatatory effects due to selective alpha 1-receptor antagonistic action and platelet antiaggregatory, antivasospastic, and vasoprotective properties due to selective 5-HT2-receptor blockade.

Contribution of serotonergic systems to maintenance of blood pressure in anaesthetised normotensive Wistar Kyoto and conscious spontaneously hypertensive rats