orthosteric

Aleniglipron (GSBR-1290) is an orally active, non-peptide GLP-1 agonist that binds to deep orthosteric pockets within transmembrane domains (TM1, TM2, and TM7). It reduces body weight and improves insulin sensitivity, making it suitable for obesity research.

Kv3 modulator 1 is an imidazolidinedione-type orthosteric modulator of Kv3 voltage-gated potassium channels. Kv3 modulator 1 reverses mechanical hyperalgesia in rat models of neuropathic and inflammatory pain, with rapid onset and sustained, dose-dependent effects. Kv3 modulator 1 can be used to study the mechanisms underlying inflammatory pain and neurological disorders such as epilepsy and schizophrenia.

Calindol hydrochloride is a potent orthosteric modulator (EC50: 132 nM) of the putative calcium-calcium-sensitive receptor (CaSR), inhibits Pi-induced VC, and delays the progression of calcification in vascular smooth muscle cells.

Upacicalcet (AJT-240) is an intraventricular calcium mimetic, a SHPT available for human hemodialysis, that inhibits excessive parathyroid hormone (PTH) secretion by directly acting on parathyroid cell membrane calcium-sensitive receptors, thereby lowering blood levels of PTH.Upacicalcet is an orthosteric modulator of calcium-sensitive receptors and prevents adenine-induced secondary vascular calcification and bone disease in a rat model of adenine-induced secondary hyperparathyroidism.

CAM 833 is an effective orthosteric inhibitor of the BRCA2-RAD51 interaction, inhibiting RAD51 aggregation, enhancing DNA damage-induced apoptosis, increasing 4N cell cycle arrest, and disrupting homologous DNA repair (HDR), and can be used for cancer therapy.

LUF6096 (CF-602) is a potent allosteric enhancer of the adenosine A3 receptor, exhibiting the capability to enhance agonist binding allosterically while demonstrating low orthosteric affinity across adenosine receptors. It displays protective effects in myocardial ischemia/reperfusion injury.

Cloransulam-methyl is an effective herbicide that is often applied to soybean fields to control broadleaf weeds.Cloransulam-methyl is rapidly metabolised in the soybean plant but is present in the soil.CBiPES hydrochloride (CBiPES HCl) is a potent orthosteric modulator of the mGlu2 receptor.

LSP4-2022 is a selective, blood-brain barrier-permeable mGlu4 orthosteric agonist (EC50 = 0.11 μM) capable of inhibiting neurotransmission in wild-type mouse cerebellar slices, exhibiting pro-depressive activity.

4,4-dimethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one is a benzodiazepine derivative. It is an orthosteric modulator of the GABAA receptor and selectively binds to the benzodiazepine site of the GABAA receptor. It has anxiolytic, anticonvulsant and sedative activity.

LY541850 is a selective orthosteric mGlu2 agonist and mGlu3 antagonist with IC50 values of 0.161 μM and 0.038 μM, respectively.LY 541850 is claimed from human ionotropic and metabotropic glutamate (mGlu) receptors expressed in non-neuronal cells.

PF-06256142 is a potent and selective orthosteric D1 receptor agonist(D1 EC50=30 nM ).

LY2979165 (mGlu2 agonist) is an orthosteric agonist of mGluR2 and can be used in studies about serving as an anti-depressant.

Padsevonil (UCB-0942) is a potential GABA A receptor orthosteric modulator with antiepileptic activity for the treatment of epilepsy.

LPPM-8 is a ligand for Med25 and acts as an inhibitor of Med25 protein-protein interactions (PPI). It engages with Med25 via the H2 surface of its activator-interaction domain, thereby stabilizing full-length proteins in the cellular proteome. LPPM-8 is an orthosteric inhibitor of H2-binding transcription activators (e.g., ATF6a). Med25 plays a role in the transcriptional regulation of RNA polymerase II-dependent genes and can form a transcription complex with ATF6α. LPPM-8 is valuable for studying the complex biology of Med25 and its Mediator complex.

Compound 4, known as β2AR ligand 1, serves as a bivalent ligand for the β2-adrenergic receptor (β2AR) at both the orthosteric binding site (OBS) and the metastable binding site (MBS).

XL-3158 is an orally active inhibitor of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) with human cGAS IC50 of 11.1 μM and murine cGAS IC50 of 2.19 μM. It binds both allosteric and orthosteric sites, stabilizing the inactive closed conformation of the enzyme, thereby weakening cGAS interaction with DNA. By targeting phase separation, XL-3158 effectively penetrates cells, reduces intracellular cGAS local concentration through inhibition of aggregate formation, and shows no significant cytotoxicity at effective concentrations, making it suitable for subsequent cellular function experiments. XL-3158 overcomes species selectivity barriers, presenting a candidate drug for cGAS-dependent inflammatory diseases.

SARM1-IN-6 (Compound 17a) is a brain-penetrant orthosteric inhibitor of SARM1. It exhibits an IC50 of 14 nM against NAM and 74 nM against HEK cells.

GABAB receptor antagonist 4 (Compound 28) is a GABAB receptor antagonist that inhibits GABA-induced G protein activation by competitively binding to the orthosteric site of the GABAB receptor. This compound is useful for researching neurological disorders associated with GABAB receptors.

ASIC1a antagonist-1 (Compound 5b) is an orthosteric non-competitive antagonist of the acid-sensing ion channel 1a (ASIC1a) with an IC50 of 27 nM at pH 6.7. It alters the pH dependency of ASIC1a activation and suppresses its maximum response. Additionally, ASIC1a antagonist-1 completely inhibits the induction of long-term potentiation (LTP) in the CA3-CA1 pathway. This compound is useful for research into brain diseases and pathologies.

XL-3156 is a potent, selective, and cross-species inhibitor of cGAS. It simultaneously occupies allosteric and orthosteric sites, stabilizing the closed conformation of the activation loop to inhibit the interaction and phase separation of cGAS with DNA. XL-3156 is applicable for research into autoimmune diseases and inflammation.

CHIPOpt is a peptide and an orthosteric inhibitor of the CHIP TPR domain, with a dissociation constant (Kd) of approximately 16 nM. It exhibits anti-aggregation properties and reduces p.tau ubiquitination, while having minimal impact on unmodified tau protein. CHIPOpt is applicable in Alzheimer's disease research.

SB405483 is a CRBN (cereblon) orthosteric ligand-binding enhancer that promotes the ubiquitination and proteasomal degradation of CRBN substrates (such as CK1α, Wee1, and IKZF1/3) by stabilizing the CRBN protein conformation and enhancing its binding affinity for substrates. SB405483 can be used in cancer research, such as in multiple myeloma and acute myeloid leukemia.

SARM1-IN-7 is a potent, orally active inhibitor of SARM1, targeting its active site (orthosteric). This compound persistently enhances SARM1's enzymatic activity, leading to exacerbated NAD depletion at suboptimal concentrations. In both cell and mouse models with activated SARM1, SARM1-IN-7 exhibits dual effects: high doses provide cell/neuron protection, whereas low doses intensify cell/neuron damage. SARM1-IN-7 is applicable in studies of axonal degeneration.

AM11542 acts as an orthosteric agonist of the cannabinoid receptor 1 (CB1), exhibiting a binding affinity with a Ki of 0.11 nM. It is useful in the investigation of CB1 receptor activation and its associated allosteric modulation mechanisms.