No abstract

The synthesis and structure-activity relationship of a novel series of compounds with combined effects on 5-HT(3A) and 5-HT(1A) receptors and on the serotonin (5-HT) transporter (SERT) are described. Compound 5m (Lu AA21004) was the lead compound, displaying high affinity for recombinant human 5-HT(1A) (K(i) = 15 nM), 5-HT(1B) (K(i) = 33 nM), 5-HT(3A) (K(i) = 3.7 nM), 5-HT(7) (K(i) = 19 nM), and noradrenergic β(1) (K(i) = 46 nM) receptors, and SERT (K(i) = 1.6 nM). Compound 5m displayed antagonistic properties at 5-HT(3A) and 5-HT(7) receptors, partial agonist properties at 5-HT(1B) receptors, agonistic properties at 5-HT(1A) receptors, and potent inhibition of SERT. In conscious rats, 5m significantly increased extracellular 5-HT levels in the brain after acute and 3 days of treatment. Following the 3-day treatment (5 or 10 (mg/kg)/day) SERT occupancies were only 43% and 57%, respectively. These characteristics indicate that 5m is a novel multimodal serotonergic compound, and 5m is currently in clinical development for major depressive disorder.

1-[2-(2,4-Dimethylphenyl-sulfanyl)-phenyl]-piperazine (Lu AA21004) is a human (h) serotonin (5-HT) 3A receptor antagonist (K i ϭ 3.7 nM), h5-HT 7 receptor antagonist (K i ϭ 19 nM), h5-HT 1B receptor partial agonist (K i ϭ 33 nM), h5-HT 1A receptor agonist (K i ϭ 15 nM), and a human 5-HT transporter (SERT) inhibitor (K i ϭ 1.6 nM) (J Med Chem 54: 3206 -3221, 2011). Here, we confirm that Lu AA21004 is a partial h5-HT 1B receptor agonist [EC 50 ϭ 460 nM, intrinsic activity ϭ 22%] using a whole-cell cAMP-based assay and demonstrate that Lu AA21004 is a rat (r) 5-HT 7 receptor antagonist (K i ϭ 200 nM and IC 50 ϭ 2080 nM). In vivo, Lu AA21004 occupies the r5-HT 1B receptor and rSERT (ED 50 ϭ 3.2 and 0.4 mg/kg, respectively) after subcutaneous administration and is a 5-HT 3 receptor antagonist in the Bezold-Jarisch reflex assay (ED 50 ϭ 0.11 mg/kg s.c.). In rat microdialysis experiments, Lu AA21004 (2.5-10.0 mg/kg s.c.) increased extracellular 5-HT, dopamine, and noradrenaline in the medial prefrontal cortex and ventral hippocampus. Lu AA21004 (5 mg/kg per day for 3 days; minipump subcutaneously), corresponding to 41% rSERT occupancy, significantly increased extracellular 5-HT in the ventral hippocampus. Furthermore, the 5-HT 3 receptor antagonist, ondansetron, potentiated the increase in extracellular levels of 5-HT induced by citalopram. Lu AA21004 has antidepressant-and anxiolytic-like effects in the rat forced swim (Flinders Sensitive Line) and social interaction and conditioned fear tests (minimal effective doses: 7.8, 2.0, and 3.9 mg/kg). In conclusion, Lu AA21004 mediates its pharmacological effects via two pharmacological modalities: SERT inhibition and 5-HT receptor modulation. In vivo, this results in enhanced release of several neurotransmitters and antidepressant-and anxiolytic-like profiles at doses for which targets in addition to the SERT are occupied. The multimodal activity profile of Lu AA21004 is distinct from that of current antidepressants.

Escitalopram is a very selective 5-HT reuptake inhibitor. It is more potent than its racemate citalopram and is effective in animal models predictive of antidepressant and anxiolytic activities.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) stress axis and disturbances in serotonin (5-HT) neurotransmission have been implicated in the pathogenesis of depressive disorder. Repeated social defeat of male NMRI mice has been shown to induce increases in core body temperature and corticosterone, indicative of a state of chronic stress in subordinate animals. The present study further characterised the HPA axis response to social defeat stress, and also examined hippocampal extracellular 5-HT release during the stress. Exposure to an acute social defeat elicits increases in plasma adrenocorticotrophic hormone and corticosterone levels, peaking at 15 and 30 min, respectively, and enhances corticotrophin-releasing factor (CRF) mRNA, but not arginine vasopressin (AVP) mRNA within the medial parvocellular division of the hypothalamic paraventricular nucleus. A concomitant increase in hippocampal corticosterone and 5-HT levels is observed. By contrast, although chronic social defeat is associated with greatly elevated corticosterone levels, the predominant drive appears to be via parvocellular AVP rather than CRF. Furthermore, subordinate animals allowed to recover for 9 days after chronic social defeat display an increase in immobility in the forced swimming model of depression, indicating that animals previously exposed to the homotypic defeat stress are sensitised to the behavioural effects of a novel stressor. These results demonstrate that social defeat induces prolonged activation of the HPA axis and alterations in 5-HT neurotransmission that could be of relevance to some of the pathological abnormalities observed in clinical depression.