A non-hallucinogenic LSD analog with therapeutic potential for mood disorders.

Hallucinations limit widespread therapeutic use of psychedelics as rapidly acting antidepressants. Here we profiled the non-hallucinogenic lysergic acid diethylamide (LSD) analog 2-bromo-LSD (2-Br-LSD) at more than 33 aminergic G protein-coupled receptors (GPCRs). 2-Br-LSD shows partial agonism at several aminergic GPCRs, including 5-HT2A, and does not induce the head-twitch response (HTR) in mice, supporting its classification as a non-hallucinogenic 5-HT2A partial agonist. Unlike LSD, 2-Br-LSD lacks 5-HT2B agonism, an effect linked to cardiac valvulopathy. Additionally, 2-Br-LSD produces weak 5-HT2A ß-arrestin recruitment and internalization in vitro and does not induce tolerance in vivo after repeated administration. 2-Br-LSD induces dendritogenesis and spinogenesis in cultured rat cortical neurons and increases active coping behavior in mice, an effect blocked by the 5-HT2A-selective antagonist volinanserin (M100907). 2-Br-LSD also reverses the behavioral effects of chronic stress. Overall, 2-Br-LSD has an improved pharmacological profile compared with LSD and may have profound therapeutic value for mood disorders and other indications.

AP-002: A novel inhibitor of osteoclast differentiation and function without disruption of osteogenesis.

AP-002 is a novel, gallium-based, anti-cancer oral compound in clinical development for cancer patients with bone metastases. We examined the effects of AP-002 on osteoclastogenesis, fusion, and osteogenesis. AP-002 exhibited a dramatic effect on osteoclast function without causing osteoclast cell death. The expression of tartrate-resistant acid phosphatase and cathepsin K mRNA levels was down-regulated in RAW264.7 cells treated with AP-002 in the presence of soluble receptor activator of NF-κB ligand. AP-002 was also found to block the fusion of osteoclasts from RAW264.7 cells. AP-002 had a similar inhibitory effect on RANKL-induced mouse primary bone marrow monocytes fusion. Human blood monocytes treated with AP-002 failed to form TRAcP/ACP5-positive cells. AP-002 caused these inhibitory effects without causing osteoclast cell death, which was in contrast to zoledronic acid controls. Furthermore, unlike zoledronic acid, AP-002 did not inhibit Rac1 activation. Gene expression analysis by microarrays showed that AP-002 significantly reverses the effects of RANKL-induced gene expression. These include several key osteoclast-differentiation/function-associated genes such as: Scinderin, OCSTAMP, Atp6v0d2, OSCAR, RhoU, Usp18, MMP9, and Trim30. The difference between AP-002 and zoledronic acid is also seen in its effects on osteogenesis. Osteoblast mineralization was promoted by AP-002 (0.1-3.0 µM), whereas zoledronic acid showed toxicity to osteoblasts at the concentration >0.5 µM, in the same dose range where it causes osteoclast cell death. Zoledronic acid therefore has no therapeutic window in its toxic effect on osteoclasts and osteoblasts. AP-002 promotes osteogenesis in this therapeutic window, while blocking osteoclast development. We therefore conclude that AP-002 has potential as a new anti-bone resorption agent, with a mechanism of action different compared with other currently marketed anti-bone resorption agents.