ABT-239 is an H3-receptor inverse agonist developed by Abbott. It has stimulant and nootropic effects, and has been investigated as a treatment for ADHD, Alzheimer's disease, and schizophrenia. ABT-239 is more active at the human H3 receptor than comparable agents such as thioperamide, ciproxifan, and cipralisant. It was ultimately dropped from human trials after showing the dangerous cardiac side effect of QT prolongation, but is still widely used in animal research into H3 antagonists / inverse agonists.
Dopamine receptor D1, also known as DRD1. It is one of the two types of D1-like receptor family — receptors D1 and D5. It is a protein that in humans is encoded by the DRD1 gene.
Neuropeptide Y receptor type 5 is a protein that in humans is encoded by the NPY5R gene.
Metabotropic glutamate receptor 2 (mGluR2) is a protein that, in humans, is encoded by the GRM2 gene. mGluR2 is a G protein-coupled receptor (GPCR) that couples with the Gi alpha subunit. The receptor functions as an autoreceptor for glutamate, that upon activation, inhibits the emptying of vesicular contents at the presynaptic terminal of glutamatergic neurons.
Metabotropic glutamate receptor 3 (mGluR3) is an inhibitory Gi/G0-coupled G-protein coupled receptor (GPCR) generally localized to presynaptic sites of neurons in classical circuits. However, in higher cortical circuits in primates, mGluR3 are localized post-synaptically, where they strengthen rather than weaken synaptic connectivity. In humans, mGluR3 is encoded by the GRM3 gene. Deficits in mGluR3 signaling have been linked to impaired cognition in humans, and to increased risk of schizophrenia, consistent with their expanding role in cortical evolution.
Eglumetad is a research drug developed by Eli Lilly and Company, which is being investigated for its potential in the treatment of anxiety and drug addiction. It is a glutamate derived compound and its mode of action implies a novel mechanism.
LY-341495 is a research drug developed by the pharmaceutical company Eli Lilly, which acts as a potent and selective orthosteric antagonist for the group II metabotropic glutamate receptors (mGluR2/3).
PEAQX is a competitive antagonist at the NMDA receptor. Although originally described as 100-fold selective for GluN1/GluN2A receptors vs. GluN1/GluN2B receptors, more detailed studies of the Ki of PEAQX revealed it only shows a 5 fold difference in affinity for GluN1/GluN2A vs. GluN1/GluN2B receptors. It is also a potent anticonvulsant in animal tests.
SB-612,111 is an opioid receptor ligand which is a potent and selective antagonist for the nociceptin receptor (ORL-1), several times more potent than the older drug J-113,397. It does not have analgesic effects in its own right, but prevents the development of hyperalgesia, and also shows antidepressant effects in animal studies.
3-( ethynyl)pyridine (MTEP) is a research drug that was developed by Merck & Co. as a selective allosteric antagonist of the metabotropic glutamate receptor subtype mGluR5. Identified through structure-activity relationship studies on an older mGluR5 antagonist MPEP, MTEP has subsequently itself acted as a lead compound for newer and even more improved drugs.
LGD-3303 is a drug which acts as a selective androgen receptor modulator (SARM), with good oral bioavailability. It is a selective agonist for the androgen receptor, producing functional selectivity with effective dissociation of anabolic and androgenic effects, acting as a partial agonist for androgenic effects, but a full agonist for anabolic effects. It has been investigated as a possible treatment for osteoporosis, and was shown in animal studies to enhance the effectiveness of a bisphosphonate drug.
Lu AA-33810 is a drug developed by Lundbeck, which acts as a potent and highly selective antagonist for the Neuropeptide Y receptor Y5, with a Ki of 1.5nM and around 3300x selectivity over the related Y1, Y2 and Y4 receptors. In animal studies it produced anorectic, antidepressant and anxiolytic effects, and further research is now being conducted into its possible medical application in the treatment of eating disorders.
Gabapentin enacarbil is an anticonvulsant and analgesic drug of the gabapentinoid class, and a prodrug to gabapentin. It was designed for increased oral bioavailability over gabapentin, and human trials showed it to produce extended release of gabapentin with almost twice the overall bioavailability, especially when taken with a fatty meal. Gabapentin enacarbil has passed human clinical trials for the treatment of restless legs syndrome, and initial results have shown it to be well tolerated and reasonably effective.
NS-11394 is a drug which acts as a subtype-selective positive allosteric modulator at GABAA receptors, with selectivity for the α3 and α5 subtypes. It has been researched as an analgesic for use in chronic or neuropathic pain.
Safotibant (INN) also known by the research code LF22-0542 is a non-peptide bradykinin B1 antagonist. It displayed binding Ki values of 0.35 and 6.5 nM at cloned human and mouse B1 receptors, respectively, while having no affinity for either human, mouse, or rat B2 receptors at concentrations up to 10 μM. This means that LF22-0542 is at least 4000 times selective for the B1 receptor over the B2 receptor. Systemic administration of LF22-0542 inhibited acute pain induced by acetic acid, formalin, and a hot plate. It also reversed acute inflammatory pain induced by carrageenan, and persistent inflammatory pain induced by CFA. In a neuropathic pain model, LF22-0542 reversed the thermal hyperalgesia, but not the mechanical hyperalgesia.
LY-235959 is a competitive antagonist at the NMDA receptor. It has analgesic and neuroprotective effects and causes hypothermia in animal models, as well as reducing the development of tolerance to morphine and altering the reinforcing effects of cocaine.
7-Chlorokynurenic acid (7-CKA) is a tool compound that acts as a potent and selective competitive antagonist of the glycine site of the NMDA receptor. It produces ketamine-like rapid antidepressant effects in animal models of depression. However, 7-CKA is unable to cross the blood-brain-barrier, and for this reason, is unsuitable for clinical use. As a result, a centrally-penetrant prodrug of 7-CKA, 4-chlorokynurenine (AV-101), has been developed for use in humans, and is being studied in clinical trials as a potential treatment for major depressive disorder, and anti-nociception. In addition to antagonizing the NMDA receptor, 7-CKA also acts as a potent inhibitor of the reuptake of glutamate into synaptic vesicles, an action that it mediates via competitive blockade of vesicular glutamate transporters.
Thienorphine is a very potent, extremely long-acting, orally-active opioid analgesic with mixed agonist–antagonist properties which was developed by the Beijing Institute of Pharmacology and Toxicology as a potential treatment for opioid dependence. It is a high-affinity, balanced ligand of the μ-, δ-, and κ-opioid receptors, behaving as a partial agonist of the μ- and κ-opioid receptors and as an antagonist of the δ-opioid receptor. It also possesses relatively low affinity for the nociceptin receptor, where it acts as an antagonist.
Sufugolix (INNTooltip International Nonproprietary Name, BANTooltip British Approved Name) (developmental code name TAK-013) is a non-peptide, orally-active, selective antagonist of the gonadotropin-releasing hormone receptor (GnRHR) (IC50Tooltip Half-maximal inhibitory concentration = 0.1 and 0.06 nM for affinity and in vitro inhibition, respectively). It was under development by Takeda for the treatment of endometriosis and uterine leiomyoma and reached phase II clinical trials for both of these indications, but was subsequently discontinued. It seems to have been supplanted by relugolix (TAK-385), which is also under development by Takeda for the treatment of these conditions and has a more favorable drug profile (including reduced cytochrome P450 inhibition and improved in vivo GnRHR antagonistic activity) in comparison.
AC-90179 is a piperidine derivative which acts as an inverse agonist at the 5-HT2A serotonin receptor and an antagonist at 5-HT2C. It was developed as a potential antipsychotic but was not pursued for medical applications due to poor oral bioavailability; however, it continues to be used as a tool compound in pharmacological research.
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