Christoph Van Amsterdam

EMD 281014, a new selective serotonin 5-HT2A receptor antagonist

The 5-HT2A receptor ligand 7-[4-[2-(4-fluoro-phenyl)-ethyl]-piperazine-1-carbonyl]-1H-indole-3-carbonitrile HCl (EMD 281014) selectively binds to human (h) and rat 5-HT2A receptors (IC50 values 0.35 and 1 nM, respectively; vs. 1334 nM for h5-HT2C) and inhibited 5-HT-stimulated [35S]guanosine 5-O-3-thiotriphosphate (GTPgammaS)-accumulation in h5-HT2A transfected Chinese hamster ovary cells (IC50 9.3 nM). EMD 28014 counteracted the N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-induced decrease of [3H]ketanserin binding in rat frontal cortex (ID50 0.4 mg/kg p.o.) and R-(-)-1-(2,5-dimethoxy-4-iodophenyl)-aminopropane (DOI)-induced head-twitch behaviour in mice (ID50 0.01 mg/kg s.c., 0.06 mg/kg p.o.), demonstrating unique selectivity and efficacy.

Mechanism of action of the bimodal antidepressant vilazodone: evidence for serotonin1A-receptor-mediated auto-augmentation of extracellular serotonin output.

RationaleThe recently approved antidepressant vilazodone, a serotonin (5-HT)1A receptor partial agonist/selective 5-HT reuptake inhibitor offers new possibilities to study the underlying mechanisms of depression pharmacotherapy and of 5-HT augmenting antidepressants.ObjectiveThe role of the 5-HT1A receptor with respect to the regulation of 5-HT output in the mechanism of action of vilazodone.MethodWe measured 5-HT levels in two subregions of the rat prefrontal cortex by microdialysis, and 5-hydroxytryptophan (5-HTP) accumulation and tissue 5-HT concentrations ex vivo.ResultsVilazodone-induced maximal 5-HT levels were similar in the medial and the lateral cortex and were up to sixfold higher than those induced by paroxetine, citalopram, or fluoxetine tested in parallel. Depolarization/autoreceptor-insensitive 5-HT release by vilazodone could be excluded. The citalopram (1xa0μM, locally infused)-induced increase of 5-HT was further increased by vilazodone (1xa0mg/kgxa0i.p.), but not by citalopram (10xa0mg/kgxa0i.p.). Unlike fluoxetine, vilazodone-induced extracellular 5-HT output was not potentiated by cotreatment with the 5-HT1A receptor blocker N-[2-(4-{2-methoxyphenyl}-1-piperazinyl)-ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY 100635). In contrast to fluoxetine, vilazodone exhibited intrinsic 5-HT1A agonist activity: it reduced, similar to (±)-8-hydroxy-2-(dipropylamino)-tetralin (8-OH-DPAT), 5-HTP accumulation in striatum and n. raphe of reserpinized rats. Hence, vilazodones agonistic actions must be 5-HT1A receptor-related since endogenous 5-HT is lacking in the reserpine-depleted animal.ConclusionsIn spite of high intrinsic 5-HT1A activity in reserpinized rats, the net effect of vilazodone at release-regulating 5-HT1A autoreceptors must be inhibitory, leading to markedly increased 5-HT output. Another possibility is that vilazodone rapidly desensitizes autoinhibitory 5-HT1A receptors by an unknown mechanism.

1-(1-Phenethylpiperidin-4-yl)-1-phenylethanols as Potent and Highly Selective 5-HT2A Antagonists

The discovery of a novel class of highly potent and selective 5‐HT2A antagonists is reported herein. Selectivity for the serotonin 5‐HT2A receptor was optimized, decreasing the affinity of these antagonists toward the adrenergic α1 and dopaminergic D2 receptors, and especially to the 5‐HT2C receptor. A series of corresponding 7‐substituted indoles is described for the first time as serotonergic ligands. The enantiomer R‐(+)‐1‐(4‐fluorophenyl)‐1‐{1‐[2‐(4‐fluorophenyl)ethyl]piperidin‐4‐yl} ethanol (R‐(+)‐74) was identified to have superior affinity for the serotonergic 5‐HT2A receptor [IC50=0.37u2005nM] and selectivity toward the dopaminergic D2‐ [IC50=2300u2005nM], adrenergic α1‐ [IC50=1000u2005nM] and 5‐HT2C receptors [IC50=490u2005nM].