G-protein Coupled Receptors and 7-TM Receptors

Diosuxentan is an inhibitor of ETA and is utilized in research pertaining to cardiovascular, renal, and neuronal inflammatory diseases.

GLP-1R agonist 33 (Compound 224) is a GLP-1 receptor agonist with potential applications in research related to diabetes, obesity, and non-alcoholic fatty liver disease (NAFLD).

Quinagolide Free Base is a non-ergot dopamine D(2)-agonist.

LRH-1 modulator-1: potent agonist, boosts IL-10, reduces IL-1b/TNFa, anti-inflammatory in gut.

<p>BNS808 is an orally active, selective CB1R antagonist with an IC50 of 0.8 nM, demonstrating significant selectivity for CB2R and minimal brain penetration. It is being studied for the treatment of obesity and related metabolic complications, such as metabolic dysfunction-associated steatotic liver disease (MASLD). BNS808 reduces drug exposure to the central nervous system, enhancing safety, and minimizes drug interactions through high plasma protein binding.</p>

GPR27 agonist-1 (compound I) is a selective agonist for GPR27 with a pEC50 value of 6.34.

L-654284 is an α2-adrenergic receptor antagonist characterized by its notable selectivity. It competes with 3H-clonidine and 3H-rauwolscine for binding in vitro, exhibiting Ki values of 0.8 nM and 1.1 nM, respectively. L-654284 effectively blocks the pre-ejaculatory effects of clonidine in isolated rat vas deferens, with a pA2 value of 9.1. The compound demonstrates significant selectivity for α2 over α1 adrenergic receptors, with a Ki value of 110 nM against 3H-prazosin binding. In vivo, L-654284 significantly increases the turnover of norepinephrine in the rat cerebral cortex, indicating its activity in blocking α2-adrenergic receptors within the central nervous system.

<p>AFP-07 is a highly selective and potent agonist. It was used for the prostacyclin receptor.</p>

Tonapofylline, orally active, selectively blocks A1 adenosine receptor (Ki: 7.4 nM), used in heart failure research.

Substituted piperidines-1 can promote the release of growth hormone in humans and animals.

5-HT2 receptor antagonist

<p>CS-0777 is a potent, selective, and orally active S1P1 agonist (sphingosine 1-phosphate receptor modulator).</p>

Pentacosafluorotridecanoic Acid (PFTrDA) is a perfluoroalkyl substance (PFAS) that exhibits various biological impacts across different species. In zebrafish embryos, exposure to PFTrDA induces yolk sac edema and increases mRNA expression of thyroid hormone synthesis genes, including tshβ, at concentrations of 0.1 and 0.3 mg/L. At a dosage of 10 mg/kg, PFTrDA reduces serum testosterone and luteinizing hormone levels, as well as palmitic acid, linoleic acid, and oleic acid levels in the testicular interstitial cells of late adolescent rats. In humans, maternal plasma levels of PFTrDA during pregnancy are positively correlated with the development of eczema in female infants (but not male infants), and PFTrDA levels are higher in the livers of cancerous humans compared to non-cancerous ones. Additionally, PFTrDA is found in marine mammals.

LK-11, an alkaloid derivative, inhibits the passive uptake of norepinephrine (NA) by synaptic vesicles in the thalamus, similarly to cocaine.

<p>AH22921 is an EP4 prostaglandin receptor antagonist with the ability to antagonize the activation of adenylyl cyclase by prostaglandins in CHO cells. It induces a rightward shift in the PGE? concentration-response curve in these cells, functioning as a non-competitive antagonist. AH22921 is selective for the EP4 receptor, inhibiting its activity in CHO cells without affecting the PGE? concentration-response curve in NPE cells that contain the EP2 receptor.</p>

L 668750 is an inhibitor of platelet-activating factor.

P2Y2 and P2Y4 receptor agonist

Disulergine is a dopamine receptor agonist. It also prolactin release-inhibiting 8 alpha-amino-ergoline.

RU 52583 is an alpha 2-adrenergic receptor antagonist.

IMP-1575 is a highly effective inhibitor of hedgehog acyltransferase (HHAT), with an IC50 of 0.75 μM when inhibiting purified HHAT. IMP-1575 has potential applications in cancer research.

<p>Rodatristat ethyl is an oral TPH1 inhibitor reducing 5-HT levels &amp; lowering PAH at low doses.</p>

<p>HU-308, a synthetic cannabinoid analogue, is a highly selective agonist of the CB2 receptor. It demonstrates an affinity for the CB2 receptor that is over 440 times greater than its affinity for the CB1 receptor, which are predominantly found in immune cells. This compound plays a crucial role in modulating the immunosuppressive effects of the endocannabinoid system (ECS). Additionally, HU-308 possesses anti-inflammatory and neuroprotective properties, and it regulates the function of microglia. Its potential applications include research into neuroinflammation and retinal diseases.</p>

AB-FUBINACA 3-fluorobenzyl isomer is a synthetic cannabinoid and an indazole derivative, exhibiting high affinity for central CB1 receptors (Ki= 0.9 nM) and possessing anticonvulsant activity.

Compound 6.4, also known as 5-HT7R antagonist 3, is a selective antagonist of the 5-HT7R with a Ki of 8 nM. It exhibits significantly less affinity towards D2R, 5-HT1AR, and 5-HT2AR with Ki values of 511 nM, 8930 nM, and 5786 nM, respectively. In mice, 5-HT7R antagonist 3 demonstrates anti-depressant and anti-anxiety activities.

Sulfinalol hydrochloride is an orally active β-adrenoceptor (β-adrenoceptor) antagonist that exhibits direct vasodilatory activity. It is also classified as an antihypertensive agent.

UMB24 is an effective antagonist of the σ2 receptor, exhibiting dissociation constants (Ki values) of 170 nM for the σ2 receptor and 322 nM for the σ1 receptor. This compound mitigates cocaine-induced convulsions and hyperactivity without causing mortality.

UNC10099984A (Compound 6) is a functionally selective ligand for the dopamine D2 receptor, exhibiting a Ki value of 4.6 nM and an EC50 of 6.2 nM for β-arrestin. This compound is useful for research into central nervous system diseases related to the D2 receptor.

O-1269 acts as a partial agonist for the cannabinoid receptor 1 (CB1R), with a binding affinity (Ki) of 32 nM. Additionally, it exhibits analgesic properties.

<p>ASN-1377642 is an NK1 receptor antagonist with a Ki value of 251 nM. It demonstrates antitumor activity in breast cancer cells with high expression of NK1R-Tr.</p>

1'-Naphthoyl-2-methylindole (Compound 88) acts as a cannabinoid mimic and an inhibitor of Win 55212-2, displaying a 34% inhibition of [3H]Win 55212-2 binding to cannabinoid receptors at a concentration of 3 μM.

ATL444 is an adenosine receptor antagonist with affinity (Ki values) for rA1AR, rA2AAR, rA2BAR, and rA3AR of 7.0, 2.5, 61.8, and >1000 nM, respectively.

(2R,3S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide is an Apelin receptor agonist

MRGPRX2 modulator-1 (example 17), a modulator of the mas-related G-protein receptor X2 (MRGPRX2), is employed in studies focused on inflammation, pain, and autoimmune disorders [1].

AM8936: potent CB1 agonist, EC50 rCB1=8.6nM/hCB1=1.4nM, Ki rat CB1=0.55nM; potential for CNS, metabolic, pain, glaucoma research.

WIN 62577 is a species-selective tachykinin NK1 receptor antagonist and also serves as an allosteric enhancer with micromolar potency at M3 receptors. Additionally, WIN 62577 demonstrates potent antiviral activity against SARS-CoV-2.

<p>Befiradol HCl (NLX-112) is a selective 5-HT1A receptor agonist with anxiolytic effects and prevents ATXN3 aggregation.</p>

<p>A2A receptor antagonist 2 is a highly selective and potent antagonist of the adenosine A2Areceptor (IC50: 8.3 nM).</p>

NK1 Receptor Antagonist 2, a compound targeting the NK1 receptor, holds potential for tinnitus and hearing loss research.

BI-685509: potent, oral sGC activator, boosts cGMP, enhances NO pathways, for CKD/DKD research.

S1PR1 agonist 2 is potent for autoimmune research (from WO2021175225A1).

<p>Rodatristat is an effective tryptophan hydroxylase 1 and TPH2 inhibitor (IC50s: 33 nM and 7 nM, respectively).</p>

<p>GRK6-IN-4 is an inhibitor of G protein-coupled receptor kinase 6 (GRK6) with an IC50 value of 1.56 μM. GRK6-IN-4 is applicable for research related to hematological malignancies, inflammatory diseases, and autoimmune disorders.</p>

U91356 is an agonist of the dopamine receptors.

Rocavorexant is an antagonist of the orexin-1 receptor (orexin-1 receptor), exhibiting a pIC50 value of 9.1 for human OX1 and a pIC50 of 6.0 for human OX2.

Potent 5-HT6/5-HT2A receptors dual antagonist with K i of 11 nM & 39 nM.

Nolpitantium besilate is a neurokinin-1 receptor antagonist.

Elsovaptan is an antagonist of the vasopressin receptor and is applicable for research in Alzheimer's disease.

<p>LY210073 is an antagonist of the Leukotriene B4 (LTB4) receptor (IC50: 6.2 nM).</p>

PGD2 is involved in allergy, asthma, sleep, temperature regulation, inhibits clotting, and relaxes blood vessels; PGDM, its metabolite, is a biomarker.

Becondogrel (2-Oxoclopidogrel) is a metabolite of Clopidogrel. It irreversibly inhibits the P2Y12 receptor, thereby preventing platelet aggregation and thrombosis.

Thielavin B, from Thielavia terricola, inhibits prostaglandin E2 synthesis and reduces rat oedema.

Potent D4R antagonist-2: selective, IC50=6.52 μM, good in vitro PK and brain penetration, potential for Parkinson's research.

Abarelix acetate: synthetic GnRHR antagonist, spikes histamine, lowers LH and testosterone temporarily, used in advanced prostate cancer.

<p>YNT-3708 is an orexin receptor (OXR) agonist, exhibiting EC50 values of 14.6 nM for OX1R and 277 nM for OX2R.</p>

GLP-1 receptor agonist 15 (Example 4) is a GLP receptor agonist with an EC50 of 0.74 nM. It exhibits an IC50 of 10.1 μM against the hERG potassium ion channel. This compound is applicable for research in the diabetes field.

AL 6598, a prodrug of PGD2 agonist AL 6556, reduces IOP by 53% at 1μg twice daily in monkeys; binds DP receptors with Ki of 3.2μM.

Cendifensine functions as a monoamine reuptake inhibitor, targeting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT).

<p>SAR-114137 is a histone sphingomyelin kinase inhibitor used in the study of molluscum arteriosum and peripheral neuropathic pain.</p>

CP-608039 is a selective adenosine A3 receptor agonist for both human A3 and human A1 receptors.

ONO-9780307 is a specific antagonist of LPA1 (lysophosphatidic acid receptor 1) (IC50: 2.7 nM).

<p>SGL5213 is a potent oral SGLT1 inhibitor (IC50: 29 nM) with potential for treating type 2 diabetes.</p>

U92016A hydrochloride: potent, orally active 5-HT1A agonist, metabolically stable, high intrinsic activity, Ki=0.2 nM.

NK-1 Antagonist 1 is a NK-1 receptor antagonist.

<p>DA-302168S is an orally active, selective GLP-1R agonist with an EC50 value of 1.32 nM. It promotes insulin secretion and has a hypoglycemic effect. Additionally, DA-302168S reduces food intake. It primarily activates GLP-1R in humans and monkeys, with minimal effect on GLP-1R in rats, mice, and dogs. DA-302168S can be used for research in type 2 diabetes and obesity.</p>

Compound 23: H3R antagonist with 170 nM Ki; inhibits AChE, BChE, hMAO B; IC50s: 180, 880, 775 nM; anti-pain, memory boost; crosses BBB. [1]

Teoprolol is a blocker of β-adrenergic receptor.

YM158 free base is a potent and selective antagonist of TXA2 and LTD4 receptor (pA2s: about 8.81 and 8.87).

DSP-1053: Benzylpiperidine-based, potent SERT inhibitor (Ki=1.02nM), partial 5-HT1A receptor agonist (Ki=5.05nM), antidepressant.

UK 432097 is an adenosine A2A agonist.

L-796778 acetate is a selective sst3 receptor agonist. In CHO-K1 cells expressing hsst3 receptors, it acts as a partial agonist that inhibits Forskolin-induced cAMP production, with an IC50 value of 18 nM. Additionally, L-796778 acetate exhibits anticonvulsant properties.

M1069 is an oral A2A/A2B receptor antagonist, 100x more selective over A1/A3, with antitumor properties by blocking adenosine's immunosuppressive effects.

Selective, high affinity competitive antagonist of the P2Y1 receptor

<p>GnRH antagonist 2 is a GnRH receptor antagonist, useful for studying endocrine diseases.</p>

APJ receptor agonist 3 is a highly effective and orally administerable agonist of the APJ receptor, demonstrating a potent EC50 value of 0.027 nM.

WIN 66306: Cyclic heptapeptide, blocks NK1/NK2 receptors, inhibits substance P-triggered contractions in guinea pig ileum.

<p>(S)-YNT-3708 is the S-isomer of YNT-3708, demonstrating relatively low activity against OX1R and OX2R receptors, with EC50 values of 3595 nM and 1661 nM, respectively.</p>

PF-07054894: potent CCR6 antagonist, targets GPCR, for inflammatory bowel disease research.

GPBAR1-IN-3 (Compound 14) is both a selective agonist for GPBAR1, with an EC50 value of 0.17 μM, and an antagonist for CysLT1R [1].

CP-199330: non-toxic alternative to Zafirlukast & Pranlukast, blocks cysteyl LT1 receptors.

LJ-4517 is an effective A2AAR antagonist (Ki=18.3 nM). LJ-4517 can effectively replace the binding of [3H] ZM241385 at WT A2AAR.

EP4 receptor antagonist 2 (compound 2-13) is a potent agonist of the EP4 receptor (IC50: 7.8 nM) and has antitumour effects.

AFP 07 free acid is a 7,7-difluoroprostacyclin derivative. It also acts as a selective and highly potent agonist for the IP receptor.

5-HT6R/MAO-B modulator 1 blocks 5-HT6R and permanently inhibits MAO-B, protects glial cells, and reverses memory loss.

L-657926 is a stereoselective antagonist of the thromboxane A2 (TxA2) receptor, composed of (-)-9-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl acetic acid and (+)-9-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl acetic acid. The IC50 values for the (-) and (+) configurations against TxA2 are 0.27 nM and 124 nM, respectively.

SB 224289: selective 5-HT1B antagonist, pKi 8.2, 60x selectivity, effective orally.

CI-624 reduces the secretion and output of hydrogen ions, sodium ions, potassium ions, and pepsin. This compound may be utilized in research focusing on cancer and autoimmune diseases.

<p>hA3AR agonist 1 is a potent human A 3 adenosine receptor (hA 3 AR) agonist (Ki = 2.40 nM) .</p>

SR2640 is a potent and highly selective LTD4/LTE4 antagonist, specifically inhibiting LTD4-induced contractions in guinea pig ileum and tracheal smooth muscle in a concentration-dependent manner, without affecting histamine-induced contractions. It blocks the binding of 0.4 nM [3H]LTD4 to guinea pig lung membrane receptors with an IC50 of 23 nM. SR2640 also causes a parallel rightward shift in the dose-response curve for LTD4-induced bronchoconstriction in guinea pigs when administered intravenously, with the degree of shift correlating positively with its dosage. SR2640 is applicable for asthma research.

Dopamine D4 receptor ligand 3 (Compound 16) functions as a dopamine D4 receptor (D4R) antagonist with a pKi of 8.86. In HEK-293T cells, it shows pIC50 values of 5.78, 5.55, and 6.17 for Go, Gi, and βArr2 sensors, respectively. This compound inhibits the activity of human glioma cell lines U87 MG, T98G, and U251 MG, and it induces ROS production and mitochondrial dysfunction in these glioma cells.

MDMB-FUBICA is a potent agonist of the cannabinoid receptors and exhibits psychoactive properties. It can be utilized in e-cigarettes.

LTD4 antagonist 1 is a potent and orally active antagonist of leukotriene D4 (LTD4; Ki: 0.57 nM).

Oral antiplatelet agent 1 is a potent antiplatelet agent with an IC50 of 2.94 μM in vitro.

CB1/2 receptor-1 (compound 5.3) serves as an agonist for CB1/2 receptors and is utilized in angiogenesis research.

Fosrolapitant is an antagonist of the neurokinin 1 (NK1) receptor.

CCR5 antagonist 1 is a CCR5 antagonist extracted from WO 2004054974 A2. It can inhibit HIV replication.

BI 639667, an azaindazole-class compound, potently inhibits CCR1 (IC50=1.8 nM in calcium flux assays).

<p>Sigma-1 receptor antagonist 6 (Compound 12), a σ1R antagonist, demonstrates significant antiallodynic effects by targeting the Sigma-1 receptor (σ1R). This compound is effective in animal models for neuropathic pain, particularly for reducing mechanical allodynia caused by paclitaxel.</p>

<p>Toladryl is a derivative of Diphenhydramine that can cross the blood-brain barrier and exhibits oral activity, with antihistamine and anticholinergic properties. Its anticholinergic effects are approximately a tenth of those seen with Diphenhydramine, yet it offers 2-4 times the protection against lethal doses of histamine in guinea pigs. The side effects of Toladryl are fewer and milder compared to Diphenhydramine; however, at higher doses, it may cause symptoms such as insomnia, agitation, and disorientation related to the central nervous system. Toladryl is utilized in the research of allergic diseases.</p>

25C-NBF hydrochloride is an agonist of 5-HT receptors, specifically activating 5-HT2A and 5-HT2C receptors, with an EC50 of approximately 0.3 μM.

LPA5 antagonist 3 (Example 74), a lysophosphatidic acid receptor 5 (LPA5) antagonist, exhibits potent activity with an IC50 value of 170 nM. It is primarily utilized in the research of pain disorders and atherosclerosis [1].