5-HT5A receptor

On March 28th, the journal "Cell" published an online research paper titled "Flexible Scaffold-based Cheminformatics Approach for Polypharmacological Drug Design". Researchers Wang Sheng, Cheng Jianjun, and Xu Huaqiang from three research teams reported a Flexible Scaffold-based Cheminformatics Approach (FSCA) for designing a dual-target, multi-efficacy active pharmaceutical compound IHCH-7179. This molecule harbors precursor drug properties with 5-HT1AR agonist activity and 5-HT2AR antagonist activity. In mouse models, it demonstrated promising results in improving mental and cognitive functions, offering new possibilities for the treatment of complex brain diseases. BackgroundLysergic acid diethylamide (LSD) is a semi-synthetic psychedelic drug belonging to the family of ergoline compounds. It was first synthesized by the Swiss chemist Albert Hofmann in 1938 from ergotamine, a natural alkaloid found in the ergot fungus that grows on rye. Hofmann accidentally ingested a small amount of LSD and personally experienced its profound psychological effects, leading to the discovery of its potential pharmacological actions. Chemically, LSD is an extremely potent hallucinogen, able to produce significant psychological effects at very small doses. Its mechanism of action primarily involves a strong agonistic effect on serotonin (5-hydroxytryptamine or 5-HT) receptors in the central nervous system, particularly the 5-HT2A receptor. This action results in the abnormal synchronization of brain neural networks, leading to a range of complex psychological experiences, including visual and auditory distortions, altered thought patterns, emotional fluctuations, and a profound transformation of self-perception and reality. Despite discussions in some research regarding the potential use of LSD in psychotherapy (such as adjunct therapy for certain mental disorders), because of its intense hallucinogenic effects and potential risks, including adverse psychological reactions (such as panic, anxiety, psychotic symptoms), long-term psychological consequences (like Hallucinogen Persisting Perception Disorder, HPPD), and the unpredictability of use in uncontrolled settings, LSD is a strictly controlled illicit substance in most countries and regions. LSD, through its ergoline ring structure, binds to various aminergic GPCRs, particularly exhibiting a strong activating effect on the 5-HT2A receptor, which is associated with its hallucinogenic effects. Atypical antipsychotic drugs, such as risperidone, improve psychotic symptoms by antagonizing the 5-HT2A receptor, where the inclusion of a fluorophenyl group contributes to multi-target effects and antagonism of both serotonin and dopamine receptors. In this study, researchers hope to generate synergistic therapeutic effects by designing bifunctional compounds that can simultaneously antagonize the 5-HT2AR and activate the 5-HT1AR. Methods and StrategiesResearchers conducted an in-depth analysis of the binding conformations of LSD and atypical antipsychotic drugs on various serotonin receptors, thereby inspiring the process of searching for and designing flexible drug scaffold structures. ·Analysis of LSD binding pattern: Researchers used computational docking techniques to dock LSD with the structures of published serotonin receptors (except for 5-HT2AR and 5-HT2BR, whose structures in complex with LSD were resolved by the research team). The main pharmacophore of LSD (ergoline ring) occupies the orthosteric binding pocket (OBP) of different serotonin receptors in a flat conformation, where the positively charged nitrogen atom forms a stable interaction with the receptor residue D3.32 through a salt bridge. LSD’s typical binding manner on serotonin receptors is insertion upwards, with its main pharmacophore and secondary pharmacophore occupying the orthosteric binding pocket (OBP) and a shallow binding pocket (SBP), respectively. ·Analysis of atypical antipsychotic drugs binding pattern: Unlike LSD, atypical antipsychotic drugs typically adopt a downward insertion binding posture on 5-HT2A/2CR and dopamine receptor D2R, with their secondary pharmacophore penetrating into the deep binding pocket (DBP) formed between helices III, V, and VI. Parts of the secondary pharmacophore, such as the 4-fluorophenyl group, interact with the receptor’s P5.50-I3.40-F6.44 motif (PIF motif) as well as the "toggle switch" residue W6.48, which promotes these residues to maintain an inactive conformation, as observed in many inactive structures of aminergic G-protein-coupled receptors. Through the comparison of different binding modes, researchers believe that the diverse binding postures of LSD and antipsychotic drugs on serotonin receptors suggest that the design of compounds with similar multitarget activity requires the ability to adapt to different receptor structural characteristics. These compounds should be capable of adjusting their conformations to fit various receptor binding pocket shapes. In addition, when designing new multitarget drugs, it is necessary to consider the conformational flexibility of the molecules, enabling them to adopt advantageous binding conformations on different receptors and achieve the intended pharmacological effects. Furthermore, for molecules with flexible, multi-cyclic skeletons, the C-N bond linking the cyclic structures is crucial; it helps the compound achieve the required conformational transitions in different receptor environments. Based on these insights, researchers hypothesize that serotonin receptor ligands composed of a flexible tricyclic or tetracyclic skeleton connected to secondary pharmacophores may adopt distinctly different conformations when binding to specific serotonin receptors. These conformations can manifest as either "reaching upward" or "bending down." Due to the different conformations ligands adopt when interacting with various receptors, their pharmacological effects will exhibit characteristics of bitonic pharmacology. As a result, they could show agonistic effects on one serotonin receptor while potentially exhibiting antagonistic effects on another. Researchers conducted their screening using two major compound libraries: first, the ChEMBL database, which contains 2.2 million compounds; and second, the Enamine company's on-demand synthesis library (offering 246,987 commercially available building blocks). All candidate compounds had to pass through a standardized screening process to ensure the selection of compounds with specific tricyclic or tetracyclic scaffolds that met design requirements. The screening criteria included the following characteristics: (1) The candidate scaffolds must be tricyclic or tetracyclic systems: wherein the first ring is an aromatic or indole ring. These two ring structures have specific chemical properties and spatial arrangements conducive to forming stable interactions with specific regions of the serotonin receptor. The second ring is required to be a non-aromatic ring containing an sp3 hybridized nitrogen atom. The hybridization state of this nitrogen atom provides the ring structure with a certain degree of stereochemistry and electronic properties, which aids in forming specific interactions with other molecular parts. The third ring should contain a protonated nitrogen atom. This positively charged nitrogen atom is suitable for serving as a linking fragment and forming salt bridges with the conserved D3.32 amino acid residue within the serotonin receptor, enhancing the ligand's affinity and selectivity for the receptor. (2) Conformational flexibility: During the screening process, particular attention was paid to the conformational flexibility provided by the C-N bond connecting the second and third rings. To quantify this flexibility, researchers used the "Plane of Best Fit (PBF)" score. The PBF score measures the propensity of a specific ring system in the unbound state to maintain either a flat or bent conformation. The criteria were set such that for flat conformations, the PBF score should be below 0.2; while for bent conformations, the PBF score should be above 0.4. This standard ensures that the selected scaffolds have significant conformational transition abilities in their free state, allowing them to adapt to the specific shape of the binding pocket when binding to different serotonin receptors, thereby realizing the expected pharmacological effect. Structure-Guided Multi-Target Ligand SelectionResearchers, based on previously published structural data of 5-HT1AR and 5-HT2AR, discovered that the shallow binding pockets (SBP) of the two receptors possess larger space compared to the deep binding pockets (DBP), sufficient to accommodate the 4-fluorophenyl moiety commonly found as an auxiliary pharmacophore in antipsychotic drugs. Consequently, they combined this known effective auxiliary pharmacophore, the 4-fluorophenyl group, with a flexible tricyclic or tetracyclic scaffold previously identified through computational screening. The aim was to create a compound whose primary pharmacophore (i.e., the scaffold) would bind tightly with the receptor's key binding regions, the orthosteric binding pockets, while the auxiliary pharmacophore would fit properly into the SBP, ensuring specific and effective binding on different receptors. For the selection of an appropriate linker, researchers noted that, in known antipsychotic drugs such as lumateperone, spiperone, and haloperidol, a 4-carbon linker (such as butyryl) successfully bridged the 4-fluorophenyl SP with the scaffold PP, achieving optimal binding at the binding sites of D2R and 5-HT2AR. The 4-carbon linker in aripiprazole also effectively inserted its PP into the SBP of 5-HT1AR. These examples suggest that a 4-carbon linker might be an ideal universal connector to ensure precise matching of the SP with the SBP of 5-HT1AR and the PP with the DBP of 5-HT2AR. Subsequently, researchers evaluated and ranked 10 virtually synthesized compounds using molecular docking techniques to screen for the most suitable candidates for chemical synthesis. They integrated structural features such as the 4-fluorophenyl group, a 4-atom linker, and R or S configurations of chiral carbons. Through the experimental synthesis and activity assessment of compounds IHCH-7162 and IHCH-7179, researchers found that both IHCH-7162 and IHCH-7179 acted as agonists at the 5-HT1AR receptor. For IHCH-7179, it functioned as a dual antagonist at the 5-HT2AR receptor for both G protein signaling pathway and β-arrestin2 signaling pathway. Meanwhile, IHCH-7162 exhibited partial agonist activity for G protein signaling, as well as antagonist activity for β-arrestin2 signaling. Researchers selected IHCH-7179 for further in vitro and in vivo evaluation because it demonstrates balanced agonistic activity at 5-HT1AR and antagonistic activity at 5-HT2AR. The tetracyclic framework of IHCH-7179 contains a chiral carbon atom, which results in the formation and identification of two enantiomers, namely (R)-IHCH-7179 and (S)-IHCH-7179. Both enantiomers exhibit agonistic activity on 5-HT1AR and antagonistic activity on 5-HT2AR.

Recently, AstraZeneca reported in detail the discovery process of the RXFP1 agonist AZD5462, currently in Phase II clinical trials, in two consecutive articles published in the top-tier journal JMC (Journal of Medicinal Chemistry). In 2013, the National Institutes of Health (NIH) in the United States identified the compound ML290 from a high-throughput screen of over 350,000 compounds. Nearly a decade afterward, AstraZeneca optimized this lead compound to ultimately develop AZD5462, which became the first orally administered small molecule RXFP1 agonist to enter clinical trials in June 2022. Relaxin Family Peptide Receptor 1 (RXFP1) is a receptor for relaxin-2, a key modulator of reproductive and cardiovascular physiology. RXFP1 is a thoroughly validated target and an important member of the pharmacologically relevant GPCR family 1c. Its activation by relaxin hormones is associated with hemodynamic effects, anti-fibrotic, and anti-inflammatory properties. Activation of RXFP1 can reduce vascular resistance and potentially affect pulmonary pressures, thereby increasing cardiac output and enhancing perfusion of central vascular beds in vital organs such as the kidneys, lungs, and the liver. The first article by AZ in JMC primarily details the discovery process from ML290 to AZ7976. The main purpose of the modifications was to enhance the activity of hRXFP1cAMP and to improve the metabolic stability of the molecule across various species, with the goal of achieving a human dosage of less than 500 mg/70 kg/day. A key transformation was the replacement of the methylenedioxyphenyl derivative fragment with the anthranilic acid fragment in ML290. Investigating the 5-position substitution on the benzoic acid ester was crucial to the hRXFP1cAMP SAR, and introducing a carboxylic acid at the 5-position improved several properties such as solubility and LogD. The second article mainly revolves around the transformation of AZ7976 into AZD5462. By optimizing the highly active, but metabolically unstable and poorly soluble hRXFP1 agonist AZ7976, the clinical candidate drug AZD5462 was identified. Structural changes were primarily reflected in the removal of the SF5 substituent and the substitution of the right-hand phenyl ring with an aliphatic fragment, further reducing the LogD. The therapeutic potential of AZD5462 was evaluated in a heart failure model of cynomolgus monkeys. After 8 weeks of treatment with AZD5462, significant improvements in functional cardiac parameters, including LVEF, were observed at weeks 9, 13, and 17, while there were no effects on heart rate or mean arterial blood pressure. Safety is of paramount importance for RXFP1 agonists aimed at chronic conditions. AZD5462 demonstrated a balanced profile of properties, including no risk of CYP450 enzyme inhibition, no risk of TDI (CYP3A4/5), no hERG toxicity risk, and no Ames toxicity risk. In vivo experiments showed that AZD5462 was well tolerated in both rats and cynomolgus monkeys, and it has successfully completed a Phase I safety study in healthy volunteers. These data suggest that AZD5462 is a small-molecule pharmacological analog of relaxin H2 signaling for RXFP1, with the potential to become a new treatment option for patients with heart failure. A search in the Synapse database for AZD5462 revealed four clinical trials, of which three Phase I trials have been completed. A Phase IIb clinical trial is set to start recruiting patients on June 10, 2024. The Phase IIb trial of AZD5462, carried out in patients with stable chronic heart failure, is a two-cohort, randomized, placebo-controlled, double-blind, multicenter, dose-range study. The main objective is to assess the impact of AZD5462 on cardiac function in participants with chronic heart failure (HF). The patent containing the compound AZD5462 is WO2022122773A1, applied for by AstraZeneca, which includes a total of 624 embodiments. In addition to AZD5462, it also provides protection for AZD3427 (recombinant peptide). The earliest priority date for patent WO2022122773A1 is December 8, 2020, and it was officially filed on December 7, 2021, and published on June 16, 2022. AstraZeneca demonstrated impressive speed, taking only a year and a half from the initial patent application to entering clinical trials. From the 25 patent applications identified via searches for the target RXFP1 and the company AstraZeneca, one composition patent application filed on June 6, 2023, WO2023237512A, indicates that AstraZeneca likely plans to combine AZD5462 with its blockbuster drug Dapagliflozin. According to the AstraZeneca financial report for 2023, sales of Dapagliflozin approached $6 billion. Currently, only one drug targeting RXFP1 has been marketed, which is serelaxin, a recombinant natural hormone analog developed by Novartis. Agonists in clinical development include the relaxin analog AZD3427 (Phase II), the small molecule AZD5462 (Phase II); Tectonic Therapeutic's TX-000045 is in Phase I clinical trials and plans to initiate Phase II within the year. On January 30, 2024, the publicly traded company AVROBIO announced the acquisition of the startup Tectonic Therapeutic, including this RXFP1 agonist, though the transaction amount was not disclosed; Moderna Therapeutics is developing the mRNA-based agonist mRNA-0184 (Phase I), which AstraZeneca acquired from Moderna on March 21, 2013, in a deal with an upfront payment of $240 million; BMS's BMS-986259 is currently preclinical with no progress. More than a decade has passed since the National Institutes of Health (NIH) in the United States first reported the structure of ML290. AstraZeneca has established a broad portfolio in this area, which not only includes the recombinant peptide AZD3427 in Phase II clinical trials but also an mRNA-based agonist, mRNA-0184 (Phase I), acquired from Moderna, and the oral small molecule AZD5462. With AZD5462 and TX-000045 nearing the commencement of Phase II patient recruitment to evaluate efficacy, enthusiasm for research and development in this field is set to reignite. We look forward to the announcement of more positive results, bringing hope to patients with cardiovascular diseases. Reference 1.Ram W. Sabnis. Novel RXFP1Modulators for Treating Heart Failure. ACS Med. Chem. Lett. 2022, 13, 1213−1214. 2.Maik Gollasch et al; RXFP1 Receptor Activation by Relaxin-2 Induces Vascular Relaxation in Mice via a Gαi2-Protein/PI3Kß/γ/Nitric Oxide-Coupled Pathway. doi: 10.3389/fphys.2018.01234. 3.Pamela Brown et al; Recent trends in medicinal chemistry and enabling technologies. Highlights from the Society for Medicines Research Conference. Drugs of the Future 2023, 48(3): 211-219.

On March 18th, Bristol Myers Squibb (BMS) announced that it had completed the acquisition of Karuna Therapeutics, a move that will further strengthen its investment portfolio in the field of neuroscience. With the acquisition finalized, Karuna Therapeutics has ceased trading on the NASDAQ Global Select Market and is now a wholly-owned subsidiary of Bristol Myers Squibb. At the end of December last year, BMS and Karuna jointly announced that the parties had reached a definitive merger agreement. According to the terms of the agreement, Bristol Myers Squibb will acquire all outstanding shares of Karuna at a cash price of $330.00 per share, with a total equity value of approximately $14 billion. After deducting the estimated cash acquired, the net transaction value is approximately $12.7 billion. Karuna is a biopharmaceutical company focused on the discovery, development, and delivery of innovative treatments that change the lives of patients with psychiatric and neurological disorders. Its lead product in development, KarXT (xanomeline-trospium), is an antipsychotic drug with a novel mechanism of action that offers unique efficacy and safety. The New Drug Application (NDA) for KarXT for the treatment of adult schizophrenia submitted by Karuna has been accepted for review by the U.S. FDA, with a Prescription Drug User Fee Act (PDUFA) target action date set for September 26, 2024. KarXT is also undergoing registrational trials exploring its potential as an adjunctive therapy to existing standard-of-care medications for schizophrenia and for the treatment of psychosis in Alzheimer's disease patients. Regarding SchizophreniaSchizophrenia is a chronic, severe, and debilitating mental disorder. When schizophrenia is active, symptoms can include delusions, hallucinations, disorganized speech, thought disorders, and a lack of motivation. There are 20 million people worldwide who suffer from schizophrenia. With treatment, most symptoms of schizophrenia can greatly improve, and the possibility of relapse can be reduced. The impact of schizophrenia is equivalent in males and females, but males may develop the disease earlier. The prevalence rate is similar worldwide. Compared to the general population, people with schizophrenia are more likely to die prematurely, mainly due to a higher prevalence of diseases such as heart disease and diabetes. The complexity of schizophrenia may help explain why there are misconceptions about the disorder. Schizophrenia does not mean a split personality or multiple personalities. Most people with schizophrenia are not more dangerous or violent than the general public. Although limited mental health resources in the community can lead to homelessness and frequent hospitalizations for individuals with schizophrenia, the belief that individuals with schizophrenia end up homeless or in hospitals is a misconception. Karuna TherapeuticsKaruna Therapeutics was established in Boston, the mecca of global biotechnology companies. Its parent company Puretech Health is revered as a respected industry leader within the Boston biotech community, founded by Daphne Zohar, who is also the founder and CEO of Puretech Health. Ms. Daphne Zohar, founder of Puretech Health, has been recognized as one of the top innovators under 35 by MIT Technology Review. She was chosen as one of the 28 top female leaders globally by BioWorld, named one of the "Top 15 Innovators" in the Boston area by The Boston Globe, recognized as a woman to watch by the Boston Business Journal, and MedCity News acknowledged her as one of the most influential women in healthcare innovation and on Twitter. Another founding figure of Puretech Health is Robert Langer, the company's key strategist working behind the scenes. He is a distinguished professor at MIT and a member of all three national academies. He has published more than 1,400 research papers and holds over 1,300 issued and pending patents worldwide. His patents have been licensed or sublicensed to more than 350 pharmaceutical, chemical, biotechnology, and medical device companies. He is a world-renowned expert in the field of biomedical engineering. Robert Langer has been successful in transforming scientific discoveries and research findings in the laboratory into real-world therapeutic methods, diagnostic reagents, devices, and medicines. According to the official website of PureTech Health, the company's vision is "Giving Life to Science." PureTech Health transforms scientific and technological advancements into practical clinical applications by creating companies. PureTech Health has incubated several subsidiaries, aiming to develop new drugs in various different directions. Among them, Karuna's mission is to advance transformative medications for patients with psychiatric and neurological disorders. In May 2012, Karuna signed an exclusive licensing agreement with Eli Lilly. Under the terms of this agreement, Eli Lilly transferred to Karuna all rights related to certain patents, regulatory documents, data records, and materials associated with Xanomeline. Karuna obtained the authority to sublicense or otherwise transfer rights related to the licensing agreement with Eli Lilly and is obliged to make commercially reasonable efforts to develop, produce, and commercialize any dosage form of Xanomeline, as well as to seek and maintain regulatory approval for human use. This collaboration resulted in the most significant R&D pipeline for Karuna: KarXT (Karuna-Xanomeline-Trospium), intended for the treatment of psychosis-related symptoms in patients with schizophrenia and Alzheimer's disease. Looking back at 2018, it was a pivotal year for Karuna Therapeutics. In mid-June, Karuna received an $8 million Wellcome Trust Award grant from the Wellcome Trust to advance its key pipeline, KarXT (Karuna-Xanomeline-Trospium), in Phase 2 clinical trials for the treatment of schizophrenia. This represented additional funding following the initial $3.8 million awarded by the Wellcome Trust to Karuna for Phase 1 clinical research of KarXT (Karuna-Xanomeline-Trospium). KarXT (Karuna-Xanomeline-Trospium) is a combination formulation comprising Trospium Chloride and Xanomeline, which works as an agonist of the muscarinic M1 and M4 receptors and as an antagonist of peripheral muscarinic receptors with restrictive properties. Karuna initiated a Phase 1 clinical study of KarXT for the treatment of schizophrenia in 2016, which was completed in mid-2017. In August, Karuna announced the completion of its Series A financing round, raising $42 million, led by ARCH Venture Partners. Among the investors in this round was an individual investor, the founder of publicly traded company SAGE Therapeutics, Steven Paul. Subsequently, Karuna announced the appointment of Steven Paul as the company's new CEO. Steven Paul possesses extensive experience in the research and development of central nervous system (CNS) drugs. He worked at Eli Lilly for 17 years, where he held several key leadership roles, including the President of Lilly Research Laboratories. At Eli Lilly, he was responsible for the company's overall R&D efforts and helped oversee the development of CNS drugs such as Zyprexa® and Cymbalta®. Most critically, he led the clinical development research of the xanomeline project at Eli Lilly for the treatment of Alzheimer's disease and obtained clinical evidence of xanomeline's antipsychotic and pro-cognitive properties. Between 2018 and 2022, Steven Paul led the rapid growth and transformation of Karuna. Karuna's Drug PipelineAccording to the latest corporate presentation by Karuna, KarXT is the company's most important research and development pipeline. In three 5-week clinical studies (EMERGENT-1/2/3), patients with schizophrenia experienced clinically meaningful improvements in symptoms. Data on patients' positive symptoms, negative symptoms, and secondary endpoints were all highly significant. The company has submitted a marketing application in the third quarter of 2023 and will continue to complete multiple long-term studies on the safety and tolerability over the next two years. Clinical trials for KarXT in the treatment of Alzheimer’s disease are also set to commence. Additionally, in February 2023, the company entered into a global exclusive licensing agreement with Goldfinch Bio for the research of TRPC4/5 candidate products. Under this agreement, Karuna will obtain the global exclusive rights to develop, manufacture, and commercialize multiple TRPC4/5 candidates, including the lead clinical-stage candidate GFB-887. Goldfinch Bio will receive an upfront payment of $15 million and up to $520 million in potential milestone payments, as well as royalties on each TRPC4/5 candidate product. Karuna will share details of the development plan for GFB-887 in the treatment of mood and anxiety disorders in the second half of 2023. Other Representative Schizophrenia Candidate DrugBrilaroxazine is a novel multimodal partial agonist for 5-HT1A, 5-HT2A, D2, D3, D4 receptors, and an antagonist for 5-HT2B, 5-HT2C, 5-HT7R, developed by Reviva Pharmaceuticals. In 2017, Reviva Pharmaceuticals published preclinical study results about Brilaroxazine as an atypical antipsychotic, indicating that Brilaroxazine could improve declarative memory and psychotic symptoms in a mouse model of schizophrenia. Furthermore, the drug also has the potential to treat idiopathic pulmonary fibrosis and pulmonary arterial hypertension. On October 30th, Reviva Pharmaceuticals announced that the global pivotal Phase 3 RECOVER trial for its investigational drug Brilaroxazine achieved positive preliminary results. Compared to placebo, a 50 mg dose of Brilaroxazine resulted in a reduction of 10.1 points in the PANSS total score (a scale that measures positive and negative syndromes of schizophrenia) at week 4, with significant statistical and clinical relevance. In terms of safety, after 4 weeks of treatment, no drug-related serious adverse events (SAEs) were observed, no treatment-emergent SAEs (TESAEs) were seen, and no significant safety concerns for Brilaroxazine were reported. Roluperidone (MIN-101) is a clinical-stage small molecule drug developed by Minerva Neurosciences that acts as a dual antagonist of the 5-HT2A receptor and sigma2 receptor. On May 10th, Minerva Neurosciences announced that the New Drug Application for Roluperidone for the treatment of negative symptoms in patients with schizophrenia has been submitted for FDA review. Ulotaront is a dual agonist of the 5-HT1A receptor and Trace Amine-Associated Receptor 1 (TAAR1), originally developed by Sumitomo Pharma, and is currently being investigated as an adjunctive therapy for the treatment of schizophrenia, generalized anxiety disorder, and major depressive disorder. On July 31st, Sumitomo Pharma announced on their official website that their antipsychotic clinical candidate drug, Ulotaront (SEP-363856), did not meet the primary endpoints in two recent Phase 3 clinical studies (DIAMOND 1 and DIAMOND 2).