G-protein Coupled Receptors and 7-TM Receptors

S1P1 agonist 4 exhibits enhanced potency with an EC 50 value of less than 0.05 mg/kg and a predicted human half-life (t1/2) of approximately 5 days, indicating

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> 100 μM; cardiac toxicity IC50= 24.5 μM). It has antidepressant properties and is useful for depression research.

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.

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

<p>Zafirlukast metabolite M1 (compound 15) is an inhibitor used in the treatment of asthma and other allergic pulmonary conditions, effectively antagonizing leukotriene activity.</p>

Nedocromil sodium is a pharmacologic stabilizer of mast cells, has been shown to normalize cytokine levels and attenuate cardiac remodeling.

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

<p>MRT-92 is an antagonist of Smoothened (Smo) with anti-cancer activity, featuring a binding affinity (Ki) of 0.7 nM. It inhibits the Hedgehog signaling pathway by obstructing the overlapping binding sites within the transmembrane domain of the Smoothened receptor and suppresses the proliferation of cerebellar granule cells in rodents (IC50=0.4 nM). MRT-92 is utilized for research into cerebellar gliomas.</p>

<p>PF-06372222: a small-molecule that modulates GCGR and antagonizes GLP-1R, affecting insulin and glucagon.</p>

TGR5 Receptor Agonist 3 is a GPBAR1 agonist with EC50 of 16.4 nM (hTGR5) & 209 nM (mTGR5), ensures gallbladder safety and reduces filling.

BMS-986120: Oral, reversible PAR4 antagonist. IC50: 9.5 nM (human), 2.1 nM (monkey). Potent, selective antiplatelet.

Dersimelagon phosphate: MC1R agonist, boosts melanin, enhances light tolerance in EPP/XLP without sun.

<p>AAZ-A 154 mesylate mesylate is a selective, competitive, and non-hallucinogenic antagonist of 5-HT2AR. It enhances neuronal growth in rodents and produces enduring beneficial behavioral effects.</p>

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

Compound 2o, also known as CB2R/5-HT1AR agonist 1, serves as a partial orally active agonist for the CB2 receptor (EC50 = 479.6 nM) and a full agonist for the 5-HT1A receptor (EC50 = 2.7 μM). This compound demonstrates both anti-anxiety and anti-depressive effects and has favorable pharmacokinetic properties [1].

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

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

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.

Vibegron (MK-4618) is an effective and selective Beta 3 adrenergic receptor agonist, used to treat overactive bladder (OAB).

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.

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

Tipindole is a serotonin antagonist utilized in research related to depression.

5-HT2A and 2C receptor antagonist

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.

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

<p>Taranabant: potent CB1 receptor inverse agonist; inhibits agonists with 0.13 nM Ki in vitro.</p>

<p>Compound 6f is a potent, selective 5-HT1A receptor blocker (Ki: 35 nM), useful in CNS disorder research.</p>

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

Monlunabant ((S)-MRI-1891), a solid dispersion compound, functions as an inhibitor of the cannabinoid CB1 receptor [1].

<p>SGLT1/2-IN-8 (compound 8) is a potent and orally active dual inhibitor of SGLT1/2, exhibiting IC50 values of 4 nM and 1 nM, respectively. It shows antihyperglycemic properties, making it suitable for related research.</p>

5-HT7R antagonist 1 is a G protein-biased antagonist with Ki of 6.5 nM for 5-HT 7R.

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

CCR7-Cmp2105 is a thiadiazole-dioxide allosteric antagonist for CCR7 with a Kd of 3 nM and IC50 of 7.3 μM against arrestin binding.

<p>SEP-363856 (SEP-856) mesylate is an orally active compound that acts as an agonist for both TAAR1 and 5-HT1A receptors. This compound exhibits antipsychotic activity in the central nervous system and has potential for the study of schizophrenia.</p>

<p>Org 274179-0 is an effective allosteric antagonist of the thyroid-stimulating hormone (TSH) receptor, with an IC50 in the nanomolar range. It fully inhibits TSH (and TSI)-mediated activation of the TSH receptor with minimal impact on the efficacy of TSH. This compound can be utilized in studies of Graves' disease (GD).</p>

Lisuride: an oral D2 dopamine agonist, ergot derivative, used in Parkinson's, migraine, and high prolactin research.

MK-0812 is a dual antagonist of the CCR2 and CCR5 receptors that can alleviate adipose inflammation in ob/ob mice.

<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>

COX-2-IN-6: Potent, selective COX-2 inhibitor; oral; IC50 0.84μM, Ki 69nM; blocks PGE2 synthesis; prevents colorectal cancer.

<p>EP4 receptor antagonist 7 (Compound 14) is an antagonist of the prostaglandin E2 (PGE2) receptor subtype EP4, with an IC50 of 1.1 nM. This compound inhibits PGE2-induced β-arrestin recruitment in HEK293 cells with an IC50 of 0.9 nM. In RAW 264.7 macrophages, it reduces the expression of PGE2-induced IL-4, macrophage mannose receptor 1 (Mrc1), chitinase-like protein 3 (Chil3), chemokine (C-X-C motif) ligand 1 (Cxcl1), triggering receptor expressed on myeloid cells 2 (Trem2), and arginase 1 (Arg1) mRNA. In the CT26 mouse colon cancer model, EP4 receptor antagonist 7, combined with an anti-PD-1 antibody, inhibits tumor growth and enhances CD8+ T cell infiltration into the tumor.</p>

<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>

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

LY 245769 is an inhibitor of leukotriene E4 (LTE4).

MK-8318 is an effective and selective antagonist of the CRTh2 receptor (Ki: 5.0 nM).

BRD50837 is a potent and selective inhibitor of Sonic Hedgehog (Shh).

8 Hydroxy PIPAT oxalate is a selective 5-HT1A receptor agonist that enhances the spontaneous release of histamine by promoting the degranulation of mast cells in guinea pig and human intestinal preparations. By activating the serotonin signaling pathway, this compound demonstrates potential in regulating gastrointestinal functions and offers insight into the management and suppression of functional gastrointestinal disorders such as irritable bowel syndrome. Its effects in increasing histamine release could play a crucial role in gastrointestinal regulation.

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

(Rac)-BI 703704 is a potent activator of soluble guanylyl cyclase (sGC).

KF26777 is a potent and selective antagonist of adenosine A3 receptor.

CVT-5440 is a selective, high-affinity (2B) adenosine receptor antagonist with good selectivity.

(+)-15-epi Cloprostenol is a synthetic analogue of prostaglandin F2α (PGF2α) and functions as a potent FP receptor agonist. The compound (+)-15-epi Cloprostenol is the 15(S) or 15β-hydroxy enantiomer of (+)-(+)-15-epi Cloprostenol. Compared to the 15(R)-(+)-15-epi Cloprostenol, this epimer exhibits significantly lower activity as an FP receptor ligand. However, the specific activity of this isomer remains inadequately studied.

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.

SSR 146977 hydrochloride is a potent, selective antagonist of the tachykinin NK 3 receptor, and it can be utilized in research on psychiatric disorders and airway inflammation [1].

<p>Ersentilide, a benzamide derivative, functions as both a β1-adrenergic receptor antagonist and an Ikr blocker. It has demonstrated efficacy in animal models of cardiac arrhythmias.</p>

Atumelnant (CRN04894) is an MC2R antagonist used in the study of congenital adrenocortical hyperplasia (CAH) and Cushing's disease (CD).

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.

SB 243213 dihydrochloride is an orally active, selective and high-affinity antagonist of 5-hydroxytryptamine (5-HT)2C receptor(pKi of 9.37 and a pKb of 9.8 for

<p>Fasitibant is a potent and selective nonpeptide kinin B2 receptor antagonist.</p>

<p>TAAR1 agonist 3 is a potent agonist of Trace Amine-Associated Receptor 1 (TAAR1) with a pEC50 value of 7.6. Additionally, it acts as a full agonist at the α2AR with a pEC50 of 6. TAAR1 agonist 3 is utilized in the research of neuropsychiatric disorders.</p>

CP-865569 is a CCR1 antagonist useful in the research of inflammatory and autoimmune diseases, including conditions such as rheumatoid arthritis and multiple sclerosis.

Cannabigerovarin (CBGV) is a compound categorized as a phytocannabinoid.

<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>

RS 61756-007 is a selective thromboxane receptor (TP) agonist.

SLF1081851 (hydrochloride), a Spns2 inhibitor, effectively inhibits S1P release with an IC50 value of 1.93 μM. This compound is instrumental in the development and functioning of the immune system [1].

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.

5-HT2 receptor antagonist

RS 12254 is a dopamine agonist and antihypertensive agent.

Dopamine D3 receptor antagonist-2 is a dopamine D3 receptor selective (Ki=2.16 nM) or multi-targeting dual ligand that shows potential effects in CNS disorders.

Compound 21a: Oral GnRH-R antagonist, IC50=0.57 nM, potent against prostate cancer/prevents LH surges.

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.

Sp-UTP-α-S serves as an activator of P2Y2 and P2Y4 receptors and is applicable in cancer research.

(S)-Praziquantel is the inactive isomer of R-praziquantel.

JKC 302 is an ET-A receptor antagonist that partially inhibits the contraction of tracheal rings in asthmatic rats induced by ET-1.

<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>

ONO-8809: Thromboxane A2 antagonist, reduces airway hyperresponse, macrophage accumulation, and MMP-9 in SHRSP brains.

9-Methyl-β-carboline is a cognitive enhancer with neuroprotective, neurorestorative, and anti-inflammatory properties. Its behavioral effects may be linked to hippocampal dopamine levels and the stimulation of dendritic and synaptic proliferation.

A1 adenosine receptor antagonist

<p>Aclidinium, a dual-action compound, serves as a long-acting muscarinic antagonist and a β2-adrenoceptor (β2-AR) agonist, exhibiting bronchodilator properties. It effectively reduces lung hyperinflation, enhances lung function, and prolongs exercise endurance time. This compound is commonly utilized in studies focusing on chronic obstructive pulmonary disease (COPD).</p>

PD 140376: Selective CCK-B/gastrin receptor antagonist radioligand for guinea pig stomach & brain.

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

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].

L 668750 is an inhibitor of platelet-activating factor.

LPA2 antagonist 3 (compound 15) serves as an Lp(a) antagonist. Lp(a) is a pathogenic risk factor for atherosclerotic cardiovascular disease (ASCVD).

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

MrgprX2 antagonist-6 is a potent antiallergic agent with inhibitory effects on mast cell degranulation.

H-Glu-Thr-OH (L-α-Glutamyl-L-threonine) is a dipeptide composed of two amino acids—glutamic acid (Glu) and threonine (Thr)—linked by a peptide bond and functions as an agonist of the extracellular calcium-sensing receptor (CaSR).

INCB-9471 HCl: a potent CCR5 antagonist, blocks monocyte migration & HIV-1.

Monohydroxy Netupitant is a highly selective antagonist of NK1 receptor, and is Netupitant metabolite.

Sitamaquine hydrochloride (WR 6026) is an orally active 8-aminoquinoline analog with antileishmanial activity. This compound inhibits mitochondrial complex II (succinate dehydrogenase) and is characterized by its lipophilic weak base properties. It rapidly accumulates in the acidic compartments of Leishmania parasites, predominantly localizing within the acidocalcisomes.

Etoperidone is an antidepressant that acts as an orally active reuptake inhibitor for serotonin (serotonin) and noradrenaline (nor-adrenaline). It demonstrates specific binding affinities (Kd) for several receptors: 36 nM at the 5-HT2 receptor, 38 nM at the α1-adrenergic receptor (α1-adrenergic receptor), 85 nM at the 5-HT1A receptor, and 570 nM at the α2-adrenergic receptor (α2-adrenergic receptor).

LK-732 is a thrombin inhibitor with antithrombotic activity. It exhibits dose-dependent inhibition in models of hypercoagulability, with an IC50 value of 1.3 mg/kg. LK-732 is used in cardiovascular and cerebrovascular research.

<p>CHF-6366: M3 antagonist &amp; β2 agonist (pKi 10.4/11.4), mild Ca channel blocker, used in COPD study.</p>

<p>K-14585 blocks PAR(2), reduces NFkappaB activity, and IL-8 response, but alone can boost IL-8.</p>

Terguride: treats hyperprolactinemia, blocks 5-HT2A/B, activates dopamine receptors, studied for PAH.

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

GRK6-IN-5 is an inhibitor of the GRK6 polypeptide, with an IC50 of 4.48 μM. GRK6-IN-5 is utilized in research focused on hematological malignancies, inflammatory diseases, and autoimmune disorders.

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

LY 292728 is a highly potent antagonist of leukotriene B4 receptor.

RGS10 modulator-1 (compound 15) is an effective regulator of RGS10. It significantly reverses IFNγ-induced expression of both RGS10 protein and mRNA, as well as COX-2 mRNA and iNOS expression triggered by IFNγ.

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>25B-NBOH hydrochloride is a phenethylamine that exhibits high affinity for serotonin (5-HT) receptors 5-HT2A and 5-HT2C, with pKi values of 8.3 and 9.4, respectively.</p>

(R)-BAY-899: R-isomer, selective LH-R antagonist, effective on hLH (IC50: 185 nM) and rLH (IC50: 46 nM), orally active.

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

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