non-classical

2,2,2-Trichloroethanol, the active form of the sedative hypnotic drug chloral hydrate, is an agonist for the nonclassical K2P channels TREK-1 (KCNK2) and TRAAK (KCNK4). It activates a nonclassical potassium channel in cerebrovascular smooth muscle and dilates the middle cerebral artery [1]. [1]. Nikhil K Parelkar, et al. 2,2,2-trichloroethanol Activates a Nonclassical Potassium Channel in Cerebrovascular Smooth Muscle and Dilates the Middle Cerebral Artery. J Pharmacol Exp Ther. 2010 Mar;332(3):803-10.

Fezolamine is a novel orally available non-tricyclic compound with antidepressant activity. It is three to two times more selective in blocking synaptosomal uptake of [3H]norepinephrine than uptake of [4H]3-hydroxytryptamine or [3H]dopamine in vitro. It blocked the inhibitory effects of rifampicin and tetraphenyl in classical behavioral tests using monoamine-depleted animals.

L-Homopropargylglycine is an alkyl chain-based PROTAC linker utilized in the synthesis of PROTACs[1].

6-Chloro-7-deazaguanine (compound 63) is an inactive IKK molecule, lacking the essential 5-cyano group, and targets IKKα and IKKβ with Ki values exceeding 30 μM. IKKβ and IKKα are central molecules in the classical and non-classical NF-κB pathways, respectively.

ARP 101 is an effective selective matrix metalloproteinase-2 (MMP-2) inhibitor with anti-cancer activity. It induces the inhibition of HCMV through non-classical chelate 1 (SQSTM1)/p62-Keap1-Nrf2 pathways and phosphorylation of the C-terminal domain of p62, regulating autophagy and inhibiting melanogenesis.

AM7499 is a non-selective cannabinoid receptor agonist with remarkably high in vitro and in vivo potency. It is readily hydrolysed by plasma esterases and to be less prone to deposition in bodily fat than existing classical cannabinoid agonists.

MS-177 is a PROTAC EZH2 degrader that promotes cholangiocarcinoma growth through the EZH2-mediated WNT7B/β-catenin pathway.MS-177 inhibits the growth of leukemia cells, induces apoptosis, and cell cycle arrest.MS-177 induces degradation of the classical EZH2-PRC2 and the non-classical EZH2-cMyc complexes and activates the immune-responsive genes in MM cells.

FHD-609 is an effective BRD9 inhibitor and PROTAC degrader, targeting the non-classical BAF (ncBAF) subunit BRD9, thereby depleting the SS18-SSX fusion protein, and can be used for the study of synovial sarcoma (SS).

Arachidoyl ethanolamide, a saturated fatty acyl ethanolamide lacking classical (CB1/CB2) activity, plays a role in a complex system comprising central cannabinoid (CB1), peripheral cannabinoid (CB2), and non-CB receptor-mediated pharmacology. This system has paved the way for extensive research in diverse fields such as memory, weight loss and appetite, neurodegeneration, tumor surveillance, analgesia, and inflammation. Unlike other compounds, Arachidoyl ethanolamide does not bind to the murine CB1 receptor nor does it compete with anandamide for the fatty acid amide hydrolase, the endocannabinoid hydrolytic enzyme. The non-CB receptor-mediated actions of saturated ethanolamides like Arachidoyl ethanolamide are currently under investigation.

Antibacterial agent 197 (compound 1-deAA) functions as a termination inhibitor targeting non-classical anhydroglycosyl receptors and anhydrowall peptide-type peptidoglycan (PG) within bacterial TGase and exhibits efficacy against Staphylococcus aureus. It acts synergistically with Vancomycin, serving as its antibacterial adjuvant [1].

Foxy-5 Ammonium Salt is a WNT5A agonist, a mimetic peptide of WNT5A, a non-classical member of the Wnt family.Foxy-5 Ammonium Salt triggers cytoplasmic free calcium signaling without affecting β-catenin activation and inhibits migration and invasion of epithelial cancer cells.Foxy-5 Foxy-5 Ammonium Salt effectively reduces the metastatic spread of prostate cancer cells with low WNT5A expression in an in situ mouse model.

NDI-Lyso is an anticancer agent targeting lysosomes, functioning through an enzyme-induced self-assembly (EISA) mechanism catalyzed by Cathepsin B. In cancer cell lysosomes, it forms rigid long fibers, promoting lysosomal swelling, lysosomal membrane permeabilization (LMP), and membrane disruption. This leads to non-classical caspase-independent apoptosis (Apoptosis). NDI-Lyso demonstrates significant selective anticancer activity across various cancer cell lines and drug-resistant cancer cells (IC50 approximately 10 μM), while exhibiting low toxicity to normal cells (IC50 > 60 μM).