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Basic & Clinical Pharmacology &... Jun 2020G protein-coupled receptors (GPCRs) constitute the largest family of receptors and membrane proteins in the human genome with ~800 members of which half are olfactory.... (Review)
Review
G protein-coupled receptors (GPCRs) constitute the largest family of receptors and membrane proteins in the human genome with ~800 members of which half are olfactory. GPCRs are activated by a very broad range of endogenous signalling molecules and are involved in a plethora of physiological functions. All GPCRs contain a transmembrane domain, consisting of a bundle of seven α-helices spanning the cell membrane, and forming the majority of the known ortho- or allosteric ligand binding sites. Due to their many physiological functions and the accessible and druggable transmembrane pocket, GPCRs constitute the largest family of drug targets mediating the actions of 34% of currently marketed drugs. GPCRs activate one or more of the four G protein families (G , G , G and G ) and/or ß-arrestin. About a third of the non-olfactory GPCRs are referred to as orphan receptors which means that their endogenous agonist(s) have not yet been found or firmly established. In this MiniReview, we focus on the orphan GPR139 receptor, for which the aromatic amino acids L-Trp and L-Phe as well as ACTH/α-MSH-related peptides have been proposed as endogenous agonists. GPR139 has been reported to activate several G protein pathways of which G is the primary one. The receptor shows the highest expression in the striatum, thalamus, hypothalamus, pituitary and habenula of the human, rat and mouse CNS. We review the surrogate agonists and antagonists that have been published as well as the agonist pharmacophore and binding site. Finally, the putative physiological functions and therapeutic potential are outlined.
Topics: Animals; Brain; Humans; Mice; Nerve Tissue Proteins; Rats; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 31132229
DOI: 10.1111/bcpt.13263 -
British Journal of Pharmacology Mar 2008The widely accepted model of G protein-coupled receptor (GPCR) regulation describes a system where the agonist-activated receptors couple to G proteins to induce a... (Review)
Review
The widely accepted model of G protein-coupled receptor (GPCR) regulation describes a system where the agonist-activated receptors couple to G proteins to induce a cellular response, and are subsequently phosphorylated by a family of kinases called the G protein-coupled receptor kinases (GRKs). The GRK-phosphorylated receptor then acts as a substrate for the binding of a family of proteins called arrestins, which uncouple the receptor and G protein so desensitizing the agonist-induced response. Other kinases, principally the second messenger-dependent protein kinases, are also known to play a role in the desensitization of many GPCR responses. It is now clear that there are subtle and complex interactions between GRKs and second messenger-dependent protein kinases in the regulation of GPCR function. Functional selectivity describes the ability of agonists to stabilize different active conformations of the same GPCR. With regard to desensitization, distinct agonist-activated conformations of a GPCR could undergo different molecular mechanisms of desensitization. An example of this is the mu opioid receptor (MOPr), where the agonists morphine and [D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO) induce desensitization of the MOPr by different mechanisms, largely protein kinase C (PKC)- or GRK-dependent, respectively. This can be best explained by supposing that these two agonists stabilize distinct conformations of the MOPr, which are nevertheless able to couple to the relevant G-proteins and produce similar responses, yet are sufficiently different to trigger different regulatory processes. There is evidence that other GPCRs also undergo agonist-selective desensitization, but the full therapeutic consequences of this phenomenon await further detailed study.
Topics: Animals; Humans; Protein Kinases; Receptors, G-Protein-Coupled; Second Messenger Systems
PubMed: 18059321
DOI: 10.1038/sj.bjp.0707604 -
Indian Journal of Cancer Mar 2022Androgen deprivation therapy (ADT) using gonadotropin-releasing hormone agonist (s) (GnRH-A) remains the backbone of advanced prostate cancer treatment. In this review,... (Review)
Review
Androgen deprivation therapy (ADT) using gonadotropin-releasing hormone agonist (s) (GnRH-A) remains the backbone of advanced prostate cancer treatment. In this review, we assessed the efficacy, safety, and convenience of administration of various GnRH-A. All GnRH-A (goserelin, triptorelin, buserelin, histrelin, and leuprorelin) have comparable potential to suppress testosterone (T) levels (≤50 ng/dL in a month and ≤20 ng/dL in 3 months). However, goserelin has shown better efficacy in maintaining T levels ≤50 ng/dL compared with leuprolide. The incidences of T escape are lower with goserelin and leuprolide than buserelin. Goserelin also has maximum benefit in prostate-specific antigen suppression. In neoadjuvant setting, when only goserelin was used, the 10-year overall survival (OS) rate was 42.6% to 86%. When either goserelin or leuprolide was used, the 10-year OS rate was 62%. As an adjuvant to radical prostatectomy, goserelin had a 10-year survival rate of 87%, and triptorelin had an 8-year survival rate of 84.6%. Goserelin further showed an absolute survival rate of 49% when used as an adjuvant to radiotherapy. The survival rates further improved when GnRH-A are used as combined androgen blockade compared with monotherapy. The frequency and severity of adverse events (hot flushes, fatigue, sexual dysfunction) are comparable among the GnRH-A. Goserelin appears to be the most convenient of all the GnRH-A for administration. Lack of conclusive comparative evidence makes it imperative to have a holistic approach of considering the patient profile and the disease characteristics to select the appropriate GnRH-A for ADT in prostate cancer.
Topics: Androgen Antagonists; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms
PubMed: 35343198
DOI: 10.4103/ijc.IJC_65_21 -
Biophysical Journal May 2021Agonists are evaluated by a concentration-response curve (CRC), with a midpoint (EC) that indicates potency, a high-concentration asymptote that indicates efficacy, and...
Agonists are evaluated by a concentration-response curve (CRC), with a midpoint (EC) that indicates potency, a high-concentration asymptote that indicates efficacy, and a low-concentration asymptote that indicates constitutive activity. A third agonist attribute, efficiency (η), is the fraction of binding energy that is applied to the conformational change that activates the receptor. We show that η can be calculated from EC and the asymptotes of a CRC derived from either single-channel or whole-cell responses. For 20 agonists of skeletal muscle nicotinic receptors, the distribution of η-values is bimodal with population means at 51% (including acetylcholine, nornicotine, and dimethylphenylpiperazinium) and 40% (including epibatidine, varenicline, and cytisine). The value of η is related inversely to the size of the agonist's headgroup, with high- versus low-efficiency ligands having an average volume of 70 vs. 102 Å. Most binding site mutations have only a small effect on acetylcholine efficiency, except for αY190A (35%), αW149A (60%), and those at αG153 (42%). If η is known, the EC and high-concentration asymptote can be calculated from each other. Hence, an entire CRC can be estimated from the response to a single agonist concentration, and efficacy can be estimated from EC of a CRC that has been normalized to 1. Given η, the level of constitutive activity can be estimated from a single CRC.
Topics: Binding Sites; Nicotinic Agonists; Receptors, Nicotinic
PubMed: 33675765
DOI: 10.1016/j.bpj.2021.02.034 -
Scientific Reports Nov 2019Agonists of β adrenergic receptors (βAR) and glucocorticoid receptors (GR) are prescribed to treat pulmonary diseases. Since ozone effects are mediated through the...
Agonists of β adrenergic receptors (βAR) and glucocorticoid receptors (GR) are prescribed to treat pulmonary diseases. Since ozone effects are mediated through the activation of AR and GR, we hypothesized that the treatment of rats with relevant therapeutic doses of long acting βAR agonist (LABA; clenbuterol; CLEN) and/or GR agonist (dexamethasone; DEX) would exacerbate ozone-induced pulmonary and systemic changes. In the first study, male 12-week-old Wistar-Kyoto rats were injected intraperitoneally with vehicle (saline), CLEN (0.004 or 0.02 mg/kg), or DEX (0.02 or 0.1 mg/kg). Since dual therapy is commonly used, in the second study, rats received either saline or combined CLEN + DEX (each at 0.005 or 0.02 mg/kg) one day prior to and on both days of exposure (air or 0.8ppm ozone, 4 hr/day x 2-days). In air-exposed rats CLEN, DEX or CLEN + DEX did not induce lung injury or inflammation, however DEX and CLEN + DEX decreased circulating lymphocytes, spleen and thymus weights, increased free fatty acids (FFA) and produced hyperglycemia and glucose intolerance. Ozone exposure of vehicle-treated rats increased bronchoalveolar lavage fluid protein, albumin, neutrophils, IL-6 and TNF-α. Ozone decreased circulating lymphocytes, increased FFA, and induced hypeerglycemia and glucose intolerance. Drug treatment did not reverse ozone-induced ventillatory changes, however, lung effects (protein and albumin leakage, inflammation, and IL-6 increase) were exacerbated by CLEN and CLEN + DEX pre-treatment in a dose-dependent manner (CLEN > CLEN + DEX). Systemic effects induced by DEX and CLEN + DEX but not CLEN in air-exposed rats were analogous to and more pronounced than those induced by ozone. These data suggest that adverse air pollution effects might be exacerbated in people receiving LABA or LABA plus glucocorticoids.
Topics: Adrenergic beta-2 Receptor Agonists; Animals; Clenbuterol; Dexamethasone; Drug Interactions; Fatty Acids; Glucocorticoids; Glucose; Interleukin-6; Lung; Lymphocytes; Male; Ozone; Rats; Rats, Wistar; Spleen; Thymus Gland; Tumor Necrosis Factor-alpha
PubMed: 31784596
DOI: 10.1038/s41598-019-54269-w -
Tijdschrift Voor Psychiatrie 2023Research suggests that cholinergic muscarinic 1 (M) and/or muscarinic 4 (M) receptors may be involved in the pathophysiology of psychotic disorders. Agonistic modulation... (Review)
Review
BACKGROUND
Research suggests that cholinergic muscarinic 1 (M) and/or muscarinic 4 (M) receptors may be involved in the pathophysiology of psychotic disorders. Agonistic modulation of these receptors can offer new treatment options.
AIM
To provide an overview of current research on the role of cholinergic M and M receptors in the development and treatment of psychoses, with special attention to the development of new drugs such as xanomeline and emraclidine.
METHOD
To obtain an overview, we searched for English-language studies published in PubMed, Embase, and PsycInfo up until June 1, 2023. We examined the role and effects of M and/or M agonists in schizophrenia. Additionally, we consulted clinical trial registers.
RESULTS
Our search strategy resulted in nine published articles on five clinical studies. These studies revealed that reduced presence of M receptors, primarily in the frontal cortex, and M receptors, primarily in the basal ganglia, are associated with psychoses. M and M receptors modulate dopaminergic activity in the ventral tegmentum and striatum through various pathways. Several M and/or M agonists, partial agonists, and positive allosteric modulators (PAMs) have been developed. Drugs exhibiting agonistic activity on M and/or M receptors, such as xanomeline-trospium (phase 2 and 3 studies) and emraclidine (phase 1b studies), have shown positive effects on cognitive and potentially negative symptoms in patients with schizophrenia.
CONCLUSION
M and/or M receptor agonists show potential as new treatment strategies for individuals with psychotic disorders. Although initial studies with xanomeline-trospium and emraclidine have shown positive results, further research is needed to assess their long-term efficacy, safety, and tolerability before these new medications can be evaluated.
Topics: Humans; Muscarinic Agonists; Psychotic Disorders; Receptor, Muscarinic M1; Receptor, Muscarinic M4
PubMed: 37947466
DOI: No ID Found -
RSC Medicinal Chemistry Jul 2021Several synthetic heterocyclic small molecules like imiquimod, resiquimod, CL097, CL075, bromopirone, tilorone, loxoribine and isatoribine demonstrated TLR7/8 agonistic... (Review)
Review
Several synthetic heterocyclic small molecules like imiquimod, resiquimod, CL097, CL075, bromopirone, tilorone, loxoribine and isatoribine demonstrated TLR7/8 agonistic activity and relatively modest structural changes in such molecules result in major variation in the TLR7 and/or TLR8 activity. A strict dependency of the electronic configuration of the heterocyclic system was also observed to influence the agonistic activity. In the present review, an evolution of imidazole based TLR7/8 agonist from imidazoquinoline based scaffold is delineated along with the elaboration of detailed structure activity relationship (SAR) in each chemotype. The structural and activity details of not only the active compounds but also the related inactive compounds are included to better understand the SAR. TLR7/8 agonists are emerging as promising vaccine adjuvant candidates and the present SAR and structural information will provide a road map towards the identification of more potent and appropriate candidates for further drug discovery.
PubMed: 34355178
DOI: 10.1039/d1md00031d -
Antibodies (Basel, Switzerland) Oct 2017Developing therapeutics that induce apoptosis in cancer cells has become an increasingly attractive approach for the past 30 years. The discovery of tumor necrosis... (Review)
Review
Developing therapeutics that induce apoptosis in cancer cells has become an increasingly attractive approach for the past 30 years. The discovery of tumor necrosis factor (TNF) superfamily members and more specifically TNF-related apoptosis-inducing ligand (TRAIL), the only cytokine of the family capable of eradicating selectively cancer cells, led to the development of numerous TRAIL derivatives targeting death receptor 4 (DR4) and death receptor 5 (DR5) for cancer therapy. With a few exceptions, preliminary attempts to use recombinant TRAIL, agonistic antibodies, or derivatives to target TRAIL agonist receptors in the clinic have been fairly disappointing. Nonetheless, a tremendous effort, worldwide, is being put into the development of novel strategic options to target TRAIL receptors. Antibodies and derivatives allow for the design of novel and efficient agonists. We summarize and discuss here the advantages and drawbacks of the soar of TRAIL therapeutics, from the first developments to the next generation of agonistic products, with a particular insight on new concepts.
PubMed: 31548531
DOI: 10.3390/antib6040016 -
Trends in Pharmacological Sciences Dec 2013Somatostatin analogs for the diagnosis and therapy of neuroendocrine tumors (NETs) have been used in clinical applications for more than two decades. Five somatostatin... (Review)
Review
Somatostatin analogs for the diagnosis and therapy of neuroendocrine tumors (NETs) have been used in clinical applications for more than two decades. Five somatostatin receptor subtypes have been identified and molecular mechanisms of somatostatin receptor signaling and regulation have been elucidated. These advances increased understanding of the biological role of each somatostatin receptor subtype, their distribution in NETs, as well as agonist-specific regulation of receptor signaling, internalization, and phosphorylation, particularly for the sst2 receptor subtype, which is the primary target of current somatostatin analog therapy for NETs. Various hypotheses exist to explain differences in patient responsiveness to somatostatin analog inhibition of tumor secretion and growth as well as differences in the development of tumor resistance to therapy. In addition, we now have a better understanding of the action of both first generation (octreotide, lanreotide, Octreoscan) and second generation (pasireotide) FDA-approved somatostatin analogs, including the biased agonistic character of some agonists. The increased understanding of somatostatin receptor pharmacology provides new opportunities to design more sophisticated assays to aid the future development of somatostatin analogs with increased efficacy.
Topics: Animals; Humans; Neuroendocrine Tumors; Phosphorylation; Receptors, Somatostatin; Signal Transduction; Somatostatin
PubMed: 24183675
DOI: 10.1016/j.tips.2013.10.001 -
Toxicological Sciences : An Official... Oct 2020Concentration/dose addition is widely used for compounds that act by similar mechanisms. But it cannot make predictions for mixtures of full and partial agonists for...
Concentration/dose addition is widely used for compounds that act by similar mechanisms. But it cannot make predictions for mixtures of full and partial agonists for effect levels above that of the least efficacious component. As partial agonists are common, we developed generalized concentration addition, which has been successfully applied to systems in which ligands compete for a single binding site. Here, we applied a pharmacodynamic model for a homodimer receptor system with 2 binding sites, the androgen receptor, that acts according to the classic homodimer activation model: Each cytoplasmic monomer protein binds ligand, undergoes a conformational change that relieves inhibition of dimerization, and binds to DNA response elements as a dimer. We generated individual dose-response data for full (dihydroxytestosterone, BMS564929) and partial (TFM-4AS-1) agonists and a competitive antagonist (MDV3100) using reporter data generated in the MDA-kb2 cell line. We used the Schild method to estimate the binding affinity of MDV3100. Data for individual compounds fit the homodimer pharmacodynamic model well. In the presence of a full agonist, the partial agonist had agonistic effects at low effect levels and antagonistic effects at high levels, as predicted by pharmacological theory. The generalized concentration addition model fits the empirical mixtures data-full/full agonist, full/partial agonist, and full agonist/antagonist-as well or better than relative potency factors or effect summation. The ability of generalized concentration addition to predict the activity of mixtures of different types of androgen receptor ligands is important as a number of environmental compounds act as partial androgen receptor agonists or antagonists.
Topics: Androgens; Binding Sites; Ligands; Receptors, Androgen
PubMed: 32726424
DOI: 10.1093/toxsci/kfaa108