GPCR/G-Protein

<p>CCK2 (CCK-B) receptor antagonist</p>

<p>LY3154207: selective, potent oral human dopamine D1 receptor PAM, low agonist activity, EC50=3 nM.</p>

<p>Revexepride, a 5-HT4 agonist, may boost CYP3A4, used for treating GERD.</p>

<p>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].</p>

<p>MRS7799 is a selective A3 Adenosine Receptor antagonist with Kd values of 0.55 nM for humans, 3.74 nM for mice, and 2.80 nM for rats. MRS7799 can be utilized in research related to neurodegenerative diseases, cancer, cardiac and cerebral ischemia, and autoimmune inflammatory diseases.</p>

<p>Sulamserod hydrochloride is a 5-HT4 receptor antagonist. It is utilized in research related to gastrointestinal disorders.</p>

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

<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.</p>

BW A868C is a potent, selective PGD2 antagonist and a BW245C analogue, inert to other prostaglandin receptors.

<p>ASP-2205, a 5-HT2C receptor agonist (human 5-HT2C receptor, EC50=0.85 nM; rat 5-HT2C receptor, EC50=2.5 nM), enhances the urethral closure reflex mediated by the genital nerve, thereby preventing urinary incontinence.</p>

<p>RF9 hydrochloride is a potent and selective Neuropeptide FF receptor antagonist that acts on hNPFF1R (Ki: 58 nM) and hNPFF2R (Ki: 7 nM).</p>

<p>Potent, selective D4R antagonist; IC50 = 6.87 µM; potential in Parkinson’s disease research.</p>

<p>BMS-986104 is a potent and selective S1P1 receptor modulator.</p>

<p>BD-1047 is a selective functional antagonist of sigma receptors. It can alleviate climbing behavior induced by Apomorphine and head twitching caused by Phencyclidine.</p>

<p>Compound 29 is a potent, CB2-selective antagonist/reverse agonist. Derivatives 23 &amp; 24 offer antinociception; 24 activates cannabinoid/TRPV1 receptors.</p>

<p>RGH-122 (compound 43), characterized as an orally active, potent, and selective hV1a receptor antagonist, demonstrates significant affinity with a K i value of 0.3 nM and an IC 50 of 0.9 nM. It exhibits microsomal stability, indicated by a CL int value of 13/28/25 μL/min/mg [1].</p>

<p>MK-3207 is a potent, oral CGRP receptor antagonist with high selectivity for human and monkey receptors, inhibiting blood flow in vivo.</p>

<p>Compound (−)-19, also known as (-)-5-HT2C agonist-3, is a selective 5-HT2C agonist exhibiting a preference for Gq signaling. It demonstrates efficiency with EC50 values for 5-HT2 receptor subtypes as follows: 5-HT2C at 103 nM, 5-HT2B at 570 nM, and 5-HT2A at 72 nM. This compound is utilized in research on antipsychotics.</p>

<p>SphK1-IN-1: SphK1 ATPase inhibitor, IC50=2.48 μM, potential for cancer research.</p>

<p>Henagliflozin (SHR3824): an oral, selective SGLT2 inhibitor, weak on SGLT1.</p>

<p>GHSR-1a agonist-1 (Compound 4b) is an orally active agonist of the human growth hormone secretagogue receptor 1a (GHSR-1a) with an EC50 of 0.49 nM. It effectively stimulates the release of endogenous growth hormone by activating GHSR-1a. Doses as low as 0.1 mg/kg (administered orally) can increase body weight and length in 4-week-old rats. GHSR-1a agonist-1 is applicable in research on pediatric growth and developmental delays.</p>

<p>SCH-900822 is a potent and selective glucagon receptor antagonist.</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>

<p>NMDAR antagonist 5 (Compound A17) is a multi-target antagonist that acts on NMDAR and monoamine transporters (SERT, DAT, and NET). It demonstrates strong NMDAR antagonistic efficacy (IC50= 0.3 μM) and effective activity on monoamine transporters (SERT IC50= 1.1 μM, DAT IC50= 0.7 μM, NET IC50= 2.7 μM). NMDAR antagonist 5 exhibits high safety with low toxicity (hepatic and renal toxicity IC50&gt; 100 μM; cardiac toxicity IC50= 24.5 μM). It has antidepressant properties and is useful for depression research.</p>

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

<p>Setomagpran is an antagonist of the mas-related G protein-coupled receptor (MRGPR) and possesses anti-inflammatory properties.</p>

<p>D3/5-HT receptor modulator-1 (compound 5i) is a selective antagonist of the dopamine D3 and 5-HT2A receptors, and a partial agonist at the 5-HT1A receptor. It exhibits Ki values of 4.5 nM, 11.9 nM, and 15.3 nM for the dopamine D3, 5-HT2A, and 5-HT1A receptors respectively. The compound shows lower affinity for the dopamine D2 receptor, 5-HT2C receptor, and hERG channel. D3/5-HT receptor modulator-1 possesses atypical antipsychotic properties.</p>

<p>SJPYT-310 is a selective PXR antagonist, exhibiting no noticeable cytotoxicity.</p>

<p>5-HT2A and 2C receptor antagonist</p>

<p>L 668750 is an inhibitor of platelet-activating factor.</p>

<p>PF-4693627 is an effective and selective microsomal prostaglandin E synthase-1 inhibitor (IC50=3 nM).</p>

<p>Acyline, a GnRH antagonist, suppresses gonadotropins and testosterone in animals and maintains the effect for 2 weeks in men with one dose.</p>

<p>Bometolol Hydrochloride is a beta-adrenergic blocking compound used for the treatment of cardiovascular disease.</p>

<p>Zaladenant is an adenosine receptor antagonist with antitumor properties.</p>

<p>BRD50837 is a potent and selective inhibitor of Sonic Hedgehog (Shh).</p>

<p>BRL-37344 is a selective β3-adrenergic receptor agonist. It significantly reduces the body weight of obese mice.</p>

<p>DCB-3503, a tylophorine analog, may treat cancer and suppress immunity by blocking protein synthesis and modulating HSC70's ATPase activity.</p>

<p>APJ receptor agonist 8 is a small molecule agonist of the APJ receptor, enhancing load-independent cardiac contractility in isolated perfused rat hearts.</p>

<p>K-8794 is an orally active and selective endothelin receptor ETB antagonist that can be utilized in cardiovascular disease research.</p>

<p>LX2761 is a stable inhibitor for SGLT1/2 with IC50s of 2.2/2.7 nM; it targets SGLT1 in the GI tract.</p>

<p>VGD071, a compound that targets sortilin, presents a promising avenue for forthcoming research utilizing mouse models of breast cancer.</p>

<p>Rivenprost, selective EP4 agonist (Ki: 0.7 nM), promotes bone growth, osteoblast differentiation, and aids wound healing.</p>

<p>L-365260 hemihydrate: selective oral CCK-B/gastrin blocker, Ki=1.9/2.0 nM, competes with guinea pig receptors.</p>

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

<p>SphK2-IN-2 (21g) is a potent and selective inhibitor of SphK2 (IC50: 0.23 μM).</p>

<p>Merigolix is a potent gonadotrophin releasing hormone (GnRH) antagonist .</p>

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

<p>Cicaprost (ZK 96480) is an IP agonist with artery relaxing effects; EC50 is 5.8 nM.</p>

<p>EP-3945 is an agonist of Mas-related G protein-coupled receptors (MRGPR), exhibiting greater potency than the small molecule agonist β-Alanine targeting MRGPRD. MRGPRs play a crucial role in inflammatory itch and pain perception. These receptors interact with Gq (MRGPRX2, MRGPRX4, and MRGPRX1 are coupled with Gq; MRGPRX2 and MRGPRD couple with Gi), with EP-3945 having an EC50 value of 211.6 nM for Gq.</p>

<p>BIIE-0246: A potent, non-peptide Y2 receptor antagonist; &gt;650-fold more selective than Y1, Y4, Y5.</p>

<p>HU 433, a synthetic cannabinoid, acts as a CB2 receptor agonist and is an enantiomer of HU 308. It provides anti-inflammatory and neuroprotective effects by binding to the CB2 receptor, primarily found on immune cells, thereby modulating immune responses and inflammation. Additionally, HU 433 influences microglial signaling pathways, particularly LPS and IFNγ-mediated routes, affecting the phosphorylation of MAPKs, including ERK1/2, JNK, p38, and Akt. This compound is valuable in researching neuroinflammation and retinal diseases.</p>

<p>MRS2179 blocks turkey P2Y1 receptor (Kb 102 nM, pA2 6.99), affects platelet aggregation, and has varying IC50s on P2 receptors.</p>

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

<p>Dopamine D3 receptor antagonist-1 is a dopamine D3 receptor selective or multi-targeting ligand with a Ki value of 1.58 nM that has demonstrated therapeutic</p>

<p>THRX-194556 is an agonist of the 5-HT4 receptor. It is applicable in the study of gastrointestinal functional disorders and Alzheimer's disease.</p>

<p>TAAR1 agonist 2 (compound 30), a full agonist at trace amine-associated receptor 1 (TAAR1) (pEC50=7.5), also displays agonistic properties at H1 receptors and activates various muscarinic acetylcholine receptors, including the M2 receptor (pEC50=5). This compound is utilized in researching neuropsychiatric diseases.</p>

<p>BI 703704, a soluble guanylate cyclase (sGC) activator, inhibits the progression of diabetic nephropathy in the ZSF1 rat [1].</p>

<p>LTB4 dimethyl amide: inhibits human neutrophil degranulation and rat lysozyme release; antagonizes LTB4 receptor on guinea pig lung membranes (Ki = 130 nM).</p>

<p>EP4 receptor agonist 3 is an activator of the EP4 receptor and is useful for research in the DSS-induced colitis mouse model.</p>

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

<p>NCATS-SM4420 (Compound A35) is an orally effective ligand for the thyroid-stimulating hormone receptor (TSHR) that inhibits the proliferation of MDA-T32 and MDA-T85 cells both in vitro and in vivo, with IC50 values of 0.71 μM and 0.38 μM, respectively. Additionally, it suppresses the metastasis of MDA-T85F1 in mice. NCATS-SM4420 holds potential for research in the field of thyroid cancer.</p>

<p>Tiprenolol hydrochloride is a β-adrenoceptor (β-adrenoceptor) antagonist. This compound is effective in eliminating ventricular arrhythmias in dogs caused by intravenous administration of adrenaline, following inhalation of halothane.</p>

Ici D1542: potent TXS inhibitor & TXA2 receptor antagonist, effective thromboxane blocker in vitro.

Sigma-2 Radioligand 2 (compound 4) exhibits low nanomolar affinity for the σ2 receptor (Ki=2.30 nM) and high subtype selectivity (Ki(σ1)/Ki(σ2) > 1500).

YGZ-331, a sedative hypnotic, acts by elevating GABA levels as a derivative of the adenosine nucleoside NGBA. It functions through activating A1R and A2aR, and inhibiting the phosphorylation of CaMKII (pCaMKII), thereby exerting its calming effects. Additionally, YGZ-331 reduces spontaneous motor activity in mice.

<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.</p>

<p>Tebideutorexant, an orexin-1 receptor antagonist, shows anti-panic effects in rodents and humans, providing a tool for stress response and psychiatric research.</p>

<p>DMPX (3,7-Dimethyl-1-propargylxanthine) is a caffeine-like compound capable of crossing the blood-brain barrier. It serves as an A2-selective adenosine receptor (AR) antagonist, effectively and selectively blocking the hypothermia and behavioral inhibition induced by A2 adenosine receptor agonists, such as NECA. DMPX is utilized in research on diseases like Parkinson's disease.</p>

<p>Alixorexton is an agonist of the orexin-2 receptor (orexin-2 receptor) and is utilized in obesity research.</p>

<p>Gemilukast (ONO-6950) is a cysteinyl leukotriene 1 and 2 receptor inhibitor that inhibits bronchoconstriction and is used in the treatment of asthma.</p>

<p>DM-4111, one of the primary monohydroxy metabolites of Tolvaptan, is an effective vasopressin V2 receptor (vasopressin V2 receptor) inhibitor. By inhibiting water reabsorption in renal tubules, it facilitates the excretion of electrolyte-free water. DM-4111 holds potential for research in cardiovascular diseases.</p>

<p>OP-2507, a prostacyclin agonist, is used potentially for the treatment of hepatic insufficiency and hypertension.</p>

<p>Dinoxyline is a potent dopamine receptor agonist, with dissociation constants (Ki values) for D1, D2, D3, and D4 receptors being 7 nM, 6 nM, 5 nM, and 43 nM, respectively. It is utilized in neuroscience research.</p>

<p>Tezosentan is an antagonist of the endothelin receptor (pA2s: 9.5, 7.7 for ETA and ETB receptors, respectively).</p>

<p>SORT1-IN-5 (compound 3) is a SORT1 inhibitor capable of crossing the blood-brain barrier. The MSOH salt form of SORT1-IN-5 exhibits a certain degree of oral bioavailability.</p>

<p>Aplaviroc, a potent CCR5 inhibitor, binds selectively, blocking HIV entry and specific monoclonal antibody attachment in vitro.</p>

<p>Elzasonan hydrochloride is a serotonin 1B and serotonin 1D receptor antagonist. It is utilized in the study of depression.</p>

<p>MRS2279 diammonium, a P2Y1 antagonist with K i 2.5 nM, IC 50 51.6 nM, blocks ADP-induced platelet aggregation, pK b 8.05.</p>

<p>LY 292728 is a highly potent antagonist of leukotriene B4 receptor.</p>

<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.</p>

<p>Compound 10o, a histamine H3 antagonist-1, functions as both a histamine H3 antagonist and a serotonin reuptake inhibitor, making it useful for research in depression [1].</p>

Anthrotainin is a tetracyclic compound that acts as an inhibitor of the binding of P substance (substance P), with an IC50 of 3 μM.

<p>Aplaviroc (AK 602), a SDP derivative, is a CCR5 antagonist. With IC50s of 0.1-0.4 nM for HIV-1Ba-L, HIV-1JRFL and HIV-1MOKW.</p>

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

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

<p>Compound 13 is a PAR-1 antagonist with a 3 nM IC50, useful for thrombosis and heart disease research.</p>

<p>ATX inhibitor 27 (Compound 31) is an ATX inhibitor. It demonstrates IC50 values of 13 nM against human autotaxin (hATX) and 23 nM against lysophosphatidylcholine (LPC). By inhibiting the ATX enzyme, ATX inhibitor 27 reduces LPA levels in the body. This compound is applicable in research related to ATX-LPA-associated conditions such as inflammation, neurodegenerative disorders, and cancer.</p>

<p>Dopamine D 3 receptor ligand is a potent, selective, high-affinity dopamine D3 receptor ligand that is 89 times more selective for D3 (Ki: 8 nM) than D2 (Ki:</p>

<p>2,3-dinor-11β-Prostaglandin F2α (2,3-dinor-11β-PGF2α) was recovered from the urine of both normal monkeys and humans when infused with radiolabeled PGD2, where</p>

<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>Udifitimod (BMS-986166) is a potent, selective, and orally active modulator of the S1P1R receptor, showing potential for research in autoimmune diseases.</p>

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

<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>

<p>Nolpitantium besilate is a neurokinin-1 receptor antagonist.</p>

<p>RBM10-8 irreversibly inhibits human sphingosine-1- phosphate lyase (hS1PL) while behaving also as an enzyme substrate.</p>

<p>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>

Macitentan n-butyl analogue, an oral ETA/ETB receptor blocker, may treat IPF and PAH.

<p>AMG-369 (AMG 247) is an S1P1/S1P5 dual agonist that delays the development of experimental autoimmune encephalomyelitis in rats.</p>

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

<p>Selective, high affinity competitive antagonist of the P2Y1 receptor</p>

<p>LPA2 antagonist 6 (example 2) acts as an antagonist of Lp(a). It inhibits the formation of Lp(a) with an IC50 value of 2.33 nM, making it useful for cardiovascular disease research.</p>

<p>FK-3657 is a non-peptide antagonist of bradykinin (BK)-B2 receptor.</p>

<p>MF-592: EP4 receptor antagonist, hEP4 IC50 3 nM, hWB IC50 78 nM, great oral PK, rat arthritis ED50 0.1 mg/kg/day, promising for development.</p>