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LY426965 [(2S)-(+)-1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]2-methyl- 2-phenyl-1-butanone monohydrochloride] is a novel compound with high affinity for the cloned human 5-hydroxytryptamine (HT)(1A) receptor (K(i) = 4.66 nM) and 20-fold or greater selectivity over other serotonin and nonserotonin receptor subtypes. Both in vitro and in vivo studies indicate that LY426965 is a full antagonist and has no partial agonist properties. LY426965 did not stimulate [(35)S]guanosine-5'-O-(3-thio) triphosphate (GTPgammaS) binding to homogenates of cells expressing the cloned human 5-HT(1A) receptor in vitro but did inhibit 300 nM 5-HT-stimulated [(35)S]GTPgammaS binding with a K(i) value of 3.07 nM. After both p.o. and s.c. administration, LY426965 blocked the lower lip retraction, flat body posture, hypothermia, and increase in rat serum corticosterone induced by the 5-HT(1A) agonist 8-OH-DPAT (8-hydroxy-2-dipropylaminotetralin). In pigeons, LY426965 dose-dependently blocked the stimulus cue induced by 8-OH-DPAT but had no 8-OH-DPAT-like discriminative properties. LY426965 completely reversed the effects of nicotine withdrawal on the auditory startle reflex in rats. In microdialysis experiments, LY426965 administered together with fluoxetine significantly increased extracellular levels of serotonin above those achievable with fluoxetine alone. In electrophysiological studies, the administration of LY426965 produced a slight elevation of the firing rate of 5-HT neurons in the dorsal raphe nucleus of anesthetized rats and both blocked and reversed the effects of fluoxetine on 5-HT neuronal activity. These preclinical results indicate that LY426965 is a selective, full 5-HT(1A) antagonist that may have clinical use as pharmacotherapy for smoking cessation and depression and related disorders.

The diphenylpyrazolidinone cholecystokinin (CCK)-B antagonist LY262691 has recently been demonstrated to decrease the number of spontaneously active dopamine (DA) cells in the ventral tegmental area (A10) and substantia nigra (A9) of the anesthetized rat. In the present study, three structural analogs of LY262691 with high selectivity for CCK-B receptors, LY262684, LY191009 and LY242040, also decreased the number of spontaneously active A10 DA cells. Neither an inactive analog (LY206890) nor a CCK-A-selective analog (LY219057) affected the number of spontaneously active A10 DA cells. L-365,260, a benzodiazepine CCK-B antagonist, also decreased the number of spontaneously active A10 DA cells. In addition, the more active optical isomer of LY262691 (LY288513) caused twice as large a decrease in the number of spontaneously active A10 DA cells as the less active optical isomer (LY288512). The diphenylpyrazolidinone CCK-B antagonists, but neither the inactive nor the CCK-A selective analog, also decreased the number of spontaneously active A9 DA cells; however, none of these compounds produced catalepsy in awake animals. Single-unit recordings indicated that LY262691 administration inhibited the activity of individual A9 and A10 DA neurons. These results indicate that the firing of A9 and A10 DA neurons is suppressed specifically by antagonism of CCK-B, but not CCK-A receptors. CCK-B antagonists may therefore represent a novel class of antipsychotic drugs. Furthermore, because CCK-B antagonists have no cataleptogenic effects, they may also have a reduced propensity for producing extrapyramidal side effects. In addition, these actions on midbrain DA neurons may contribute to the known anxiolytic activity of CCK-B antagonists.