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At least 19 recordsLinked to original sources
PubMed2026

Identification of CXCL13 as an agonist and CXCL11 as an inverse agonist for the viral G protein-coupled receptor ORF74.

Kaposi's sarcoma-associated herpesvirus (KSHV) establishes latent infection in humans, but under conditions of immune suppression, it may reactivate and contribute to severe diseases, including Kaposi's sarcoma (KS) and B-cell malignancies. The KSHV genome encodes a single G protein-coupled receptor (GPCR), open reading frame 74 (ORF74), which shows homology to human chemokine receptors. Since its identification in 1996, ORF74 has subsequently been shown to interact with a broad range of human CXC chemokines, as well as CCL1 and the viral chemokine vCCL2. Compared with many human chemokine receptors, ORF74 displays high basal activity. These properties allow ORF74 to deregulate host cellular pathways through constitutive and chemokine-modulated signaling. In this study, we evaluated several human chemokines that, to our knowledge, had not previously been tested in ORF74-dependent cellular assays. Whereas CXCL9, CXCL14, CXCL16 and CXCL17 did not interact with ORF74, CXCL13 was identified as an additional ORF74 agonist and CXCL11 as an inverse agonist. CXCL13 dose-dependently induced ORF74-mediated Ca2+ release, β-arrestin1/2 recruitment and chemotaxis, and enhanced basal nuclear factor κB (NF-κB) activity in ORF74-expressing cells. In contrast, CXCL11 showed no detectable ORF74 agonist activity in the calcium mobilization or chemotaxis assay, but antagonized CXCL1-induced responses in both readouts. CXCL11 also elicited inverse agonist-like responses in β-arrestin1/2 recruitment assays and reduced basal NF-κB signaling. Our study thus reveals CXCL13 and CXCL11 as two additional chemokine ligands for ORF74, further expanding the pharmacological profile of this viral GPCR.

Humans↗
PubMed1979

Acute effects of opiate agonists, partial agonists and antagonists on brain monoamines in the rat.

Single doses of 4.5 mg/kg of the opiate agonist, morphine, the partial agonists, cyclazocine, pentazocine, levallorphan and nalorphine, the antagonists, naloxone and naltrexone and dextrorphan were injected i.p. in groups of rats. Behaviour was noted for 30 min following injection and at this time, brains were removed and levels of noradrenaline (NA), dopamine (DA), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined spectrophotofluorimetrically. Only morphine and cyclazocine altered behaviour and 5-HIAA was the only substance which was consistently elevated by all the compounds tested. These results indicate that a causal relationship between the acute effects of opiate agonists, partial agonists and antagonists on brain 5-HT metabolism and their pharmacological actions is unlikely.

Animals↗
PubMed2026

Effects of GLP-1 Receptor Agonists and Dual GIP/GLP-1 Receptor Agonists on Inflammatory and Metabolic Biomarkers in Type 2 Diabetes: A Systematic Review and Meta-Analysis.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual GIP/GLP-1 receptor agonists improve cardiovascular outcomes in type 2 diabetes mellitus (T2DM), but their effects on inflammatory and oxidative biomarkers are not fully defined. MATERIALS AND METHODS: We searched PubMed, Ovid MEDLINE, Scopus, Web of Science and the Cochrane Library from inception to 19 February 2026 for randomised controlled trials (RCTs) in adults with T2DM comparing a GLP-1RA or dual GIP/GLP-1 agonist with placebo or active therapy, and reporting C-reactive protein (CRP or high-sensitivity CRP [hs-CRP]), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), malondialdehyde (MDA) or adiponectin. Random-effects meta-analyses were conducted using standardised mean differences (SMDs). RESULTS: Forty-one RCTs were included. GLP-1RAs significantly reduced CRP/hs-CRP (27 studies, 1991 participants; SMD -0.37, 95% CI -0.59 to -0.14) and MDA (3 studies, 272 participants; SMD -0.98, 95% CI -1.65 to -0.30), and increased adiponectin (16 studies, 1327 participants; SMD 0.30, 95% CI 0.13 to 0.46). Pooled effects on IL-6 (17 studies, 1068 participants; SMD -0.14, 95% CI -0.37 to 0.10), TNF-α (16 studies, 1164 participants; SMD -0.25, 95% CI -0.61 to 0.12) and MCP-1 (7 studies, 450 participants; SMD -0.27, 95% CI -0.58 to 0.03) were not statistically significant, although MCP-1 decreased in sensitivity analyses. Across biomarkers, heterogeneity was moderate to high. Two tirzepatide RCTs (562 participants) showed a significant reduction in IL-6 (SMD -0.28, 95% CI -0.47 to -0.09) and a non-significant trend towards lower CRP/hs-CRP. CONCLUSIONS: In adults with T2DM, incretin-based therapies consistently lower CRP/hs-CRP, reduce oxidative stress (MDA) and increase adiponectin, while effects on IL-6 and TNF-α are more variable. These data support a selective anti-inflammatory and metabolic regulatory profile of GLP-1-based therapy, but heterogeneity and limited data for some biomarkers warrant cautious interpretation and further mechanistic studies. TRIAL REGISTRATION: PROSPERO number: CRD420261321430.

Humans↗
PubMed1979

History and development of mixed opioid agonists, partial agonists and antagonists.

1 A brief history of the development of narcotic antagonists is outlined. 2 The clinical and pharmacological observations leading to the discovery of dualism of opiate receptors are reviewed. 3 An extension of this theory to a three-receptor model (mu, kappa and sigma) is required to rationalize the pharmacology of the antagonists analgesics cyclazocine, pentazocine and nalorphine. 4 The methodologies available for the study of compounds with dual agonist-antagonist activity are discussed in the light of the above receptor multiplicity, and data appertaining to the kappa-partial agonist, nalorphine and the mu-partial agonist buprenorphine are outlined.

Animals↗
PubMed2026

GLP-1 Receptor Agonist and GIP/GLP-1 Receptor Dual Agonist Therapeutics at the Intersection of Alcohol Use Disorder, Obesity, and Cardiometabolic Dysfunction.

The co-occurrence of metabolic dysfunction and heavy alcohol consumption contributes substantially to global morbidity, particularly through its impact on liver disease progression. Glucagon-like peptide-1 receptor (GLP1R) agonists and glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP1R dual agonists, currently approved for the treatment of diabetes and obesity and under investigation for metabolic dysfunction-associated steatohepatitis, are considered for repurposing to reduce alcohol consumption and stabilize metabolic health in heavy-drinking populations. This review summarizes existing evidence, highlights ongoing research, and outlines key unanswered questions regarding this therapeutic potential and the paradigm shift toward metabolic circuit-based interventions in addiction treatment. The dual-target GIPR/GLP1R approach could fill a critical gap for individuals struggling with both heavy alcohol consumption and metabolic dysfunction.

Alcohol use disorder↗
PubMed1979

Functional consequences of agonist-mediated state transitions in the cholinergic receptor. Studies in cultured muscle cells.

Parameters associated with activation and desensitization of the nicotinic receptor in the BC3H-1 muscle cell line have been compared with the state transitions that result upon combination with agonist. 125I-labeled cobra alpha-toxin is found to bind to an apparent single class of surface nicotinic receptors on the cells in situ with a rate constant of 1.15 x 10(5) M-1 s-1. The competition between cholinergic ligands and alpha-toxin reveals that agonists, but not classical antagonists, will promote a slow conversion to a receptor state where the affinity for agonists is enhanced. Moreover, agonists such as carbamylcholine elicit a permeability increase to 22Na+ ions that slowly decrements at a rate and to an extent closely paralleled by the conversion of the receptor to the high affinity state. Upon removal of the agonist, both the affinity increase and the diminished permeability change are completely reversible and again exhibit similar kinetics for their return to the original state. A comparison of the capacity of full agonists to compete with alpha-toxin binding and elicit a permeability change suggests that in the absence of agonist, receptor predominates in a low affinity activatable state. Binding of agonists to the low affinity state exhibits little if any cooperativity (n = 0.97 to 1.31), while the corresponding permeability change appears more cooperative (n = 1.31 to 1.52). By contrast, when receptors have been previously equilibrated with agonists, occupation of the receptor occurs over a 3- to 5-fold lower concentration range. Binding following equilibration closely correlates with a concomitant decrease in activatable receptor resulting from equivalent exposure to agonist. Furthermore, under equilibrium conditions, the binding of full agonists is typified by a moderate degree of homotropic cooperativity (1.25 to 1.44), enabling the receptor to desensitize over a narrow range of agonist concentration. Simultaneous measurement of occupation and activation parameters has enabled us to compare a state function for desensitization which is generated from binding parameters with the reduction in permeability seen in the desensitization process. A scheme describing the association of agonist with two functionally distinct receptor states is developed to account for the cooperative relationship between agonist binding and desensitization of the receptor.

Animals↗
PubMed1978

A comparison of current-voltage relations for full and partial agonists.

1. Local conductance changes produced by various bath-applied agonists at frog end-plate membrane were measured using focal recording of extracellular potential in voltage-clamped muscle fibres. The potential difference between a focal micropipette placed on the nerve terminal and another micro-pipette placed on or near inactive membrane was taken as proportional to the agonist-induced current through a small patch of an end-plate membrane. 2. The current-voltage (I--V) relation of active membrane was obtained directly by increasing the membrane potential in a ramp fashion. The change in membrane potential was slow enough for post-synaptic gating processes to reach equilibrium during the ramp. 3. During application of sufficiently low concentrations of full agonists (carbachol, (ACh) and partial agonists (choline and decamethonium) the I--V relation of end-plate membrane showed strong curvature in the range of -60 to -130 mV. The slope of I--V relations increased exponentially with membrane hyperpolarization, an e-fold change in conductance occurring for about 50 mV potential shift. 4. The curvature of the I--V relation of end-plate-membrane activated by the partial agonists choline and decamethonium became less as the agonist concentration was increased, and with high concentrations (choline 15 mM; decamethonium 250 micrometer) the I--V relation became almost straight. 5. When end-plate currents produced by high concentrations of partial agonists were matched by application of equi-active concentrations of carbachol, the carbachol-activated membrane still showed as much curvature in its I--V relation as when low concentrations of carbachol were used. 6. Choline and decamethonium concentrations for which the I--V relation was straight produced much greater depression of miniature end-plate currents than did carbachol concentrations which produced the same membrane current at the holding potential. 7. I--V relations for full agonists at high concentrations were obtained after alpha-bungarotoxin pre-treatment. During application of carbachol (400--500 micrometer) and ACh (30--40 micrometer; after complete inhibition of acetylcholinesterase activity) the I--V relation of end-plate membrane is much less curved than during application of low concentrations. 8. It is concluded that either the voltage sensitivity of agonist-induced end-plate conductance reflects voltage sensitivity of agonist binding, or the partial agonists used can exert a voltage-dependent 'local anaesthetic' action in addition to their agonist activity.

Acetylcholine↗
PubMed1977

Interactions between the effects of alpha- and beta-adrenoceptor agonists and adenine nucleotides on the membrane potential of cells in guinea-pig liver slices.

1 The beta-adrenoceptor agonist isoprenaline normally causes only a small and inconsistent increase in the membrane potential of cells in guinea-pig liver slices, in contrast to the large hyperpolarizations seen with alpha-agonists. However, after a selective alpha-adrenoceptor agonist has been applied, the response to isoprenaline becomes greatly enhanced. 2 Simultaneous application of small doses of an alpha- and beta-agonist produce hyperpolarizations larger than the sum of the responses to each agent alone. 3 These interactions occur with a range of sympathomimetic amines, including some which are not substrates for various processes for the uptake and inactivation of catecholamines. 4 Hyperpolarizations caused by externally applied cyclic adenosine-3',5'-monophosphate (cyclic AMP) also become larger after application of an alpha-agonist. 5 The adenine nucleotides adenosine 5'-diphosphate (ADP) and adenosine 5'-triphosphate (ATP) hyperpolarize guinea-pig liver cells in the dose range 0.1-1.0 mM. This response is not increased after an alpha-agonist. However, ADP and ATP are themselves able to enhance the response to beta-agonists. 6 These interactions between alpha-agonists, beta-agonists and adenine nucleotides seem to involve steps subsequent to receptor activation. Changes in the intracellular actions of cyclic AMP may be concerned.

Adenosine Diphosphate↗
PubMed1976

Selectivity of beta-adrenoceptor agonists and antagonists on bronchial, skeletal, vascular and cardiac muscle in the anaesthetized cat.

1 The potencies of fifteen beta-adrenoceptor agonists of widely differing chemical structures were compared with that of (-)-isoprenaline on bronchial muscle, soleus muscle, blood pressure and heart rate in the anaesthetized cat. The beta-adrenoceptor antagonist potencies of propranolol and practolol were determined against (-)-isoprenaline in the same model. 2 (-)-Isoprenaline was the most potent agonist and its action was essentially unselective. Thus, on all four parameters the minimal effective dose was 0.003-0.01 mug/kg and maximal or near maximal responses were produced by 0.3-1 mug/kg. Trimetoquinol was also an essentially unselective agonist. 3 For thirteen of the remaining fourteen agonists, potency was similar on bronchial muscle, soleus muscle and blood pressure but significantly lower on heart rate. 4 The remaining agonist - AH 7616 (4-hydroxy-alpha1-[[(1-methyl-3,3-diphenyl-propyl)amino]-methyl]-m-xylene-alpha1, alpha3-diol, acetate) - was also significantly less potent on heart rate than on the other parameters; in addition, it was clearly less potent on soleus muscle and blood pressure than on bronchial muscle when 5-hydroxytryptamine (5-HT) was used to induce bronchospasm. However, when acetylcholine was used instead of 5-HT the potency of AH 7616 on induce bronchospasm. However, when acetylcholine was used instead of 5-HT the potency of AH 7616 on bronchial muscle, soleus muscle and blood pressure was very similar. AH 7616 may therefore possess a specific 5-HT antagonist action in addition to its beta-adrenoceptor agonist action. 5 The fifteen test agonists were longer acting than (-)-isoprenaline and this was particularly true of trimetoquinol and soterenol. 6 The beta-adrenoceptor antagonist potency of propranolol was almost identical on bronchial muscle, soleus muscle and blood pressure and very slightly lower on the heart. Practolol was 10-12 times more potent on the heart than on bronchial muscle, soleus muscle and blood pressure. 7 These findings suggest that it may not be possible to separate the bronchodilating and tremorenhancing properties of beta-adrenoceptor agonists. The results with agonists and antagonists are in accord with Lands' dual beta-adrenoceptor sub-classification.

Adrenergic beta-Agonists↗
PubMed1976

Dissociation constants and relative efficacies of agonists acting on alpha adrenergic receptors in rabbit aorta.

The dissociation constants (KA values) of l-norepinephrine (l-NE) and seven other agonists acting on alpha adrenergic receptors in rabbit aorta strips were determined by analysis of concentration-response data before and after fractional inactivation of receptors with Dibenamine. In experiments to determine KA values, propranolol was added to block activation of beta receptors and cocaine to block the neuronal uptake mechanism. The KA of l-NE and the KA of a second agonist, when determined on paired strips from the same aorta, were used to calculate the relative affinity and the relative efficacy (er) of the second agonist as compared to l-NE. The validity of the method used for determining KA and er values was supported by the following findings. 1) The dissociation constant (KB) of the competitive antagonist, phentolamine, determined with each of the agonists, was the same as that determined with l-NE. 2) The KA determined for l-NE was independent of the fraction of active receptors remaining (q) after pretreatment with different concentrations of Dibenamine. 3) The KB of phentolamine determined with l-NE as the agonist was the same before and after fractional inactivation of receptors. 4) After inactivation in paired strips by equal exposures to Dibenamine, the q value determined with each agonist was the same as that determined with l-NE. The mean KA value for l-NE was 3.39 +/- 0.15 X 10(-7) M. The mean relative affinities of the agonists for the alpha receptor were: l-NE, 1;L-EPINEPHRINE, 1.25; L-PHENYLEPHRINE, 0.200; L-norphenylephrine, 0.217; epinine, 0.136; dopamine, 0.0055; l-alpha-methylnorepinephrine, 0.095; dl-alpha-ethylnorepinephrine, 0.0048. The mean er of each agonist was not significantly different from that of l-NE, except for l-norphenylephrine with an e of 0.71, and dl-alpha-ethylnorepinephrine with an er of 0.41. The results are discussed from the standpoint of structure-activity relationships.

Adrenergic alpha-Agonists↗
PubMed1975

Relative pre- and postsynaptic potencies of alpha-adrenoceptor agonists in the rabbit pulmonary artery.

The rabbit pulmonary artery contains postsynaptic alpha-adrenoceptors which meidate smooth muscle contraction; its noradrenergic nerves contain presynaptic alpha-adrenoceptors which mediate inhibition of the release of the transmitter evoked by nerve impulses. Dose-response curves for the pre- and postsynaptic effects of eight alpha-receptor agonists were determined on superfused strips of the artery in the presence of cocaine, corticosterone and propranolo. 1. According to the concentrations which caused 20% of the maximal contraction (EC20 post), the postsynaptic rank order of potency was: adrenaline greater than noradrenaline greater than oxymetazoline greater than naphazoline greater than phenylephrine greater than tramazoline greater than alpha-methylnoradrenaline greater than methoxamine. The pA2 values of phentolamine againstoxymethazoline, phenylephrine, alpha-methylnoradrenaline and methoxamine were 7.43, 7.48, 7.59 and 7.69, respectively. 2. For the investigation of presynaptic effects, the arteries were preincubated with 3H-noradrenaline. All agonists inhibited the overflow of tritium evoked by transmural sympathetic nerve stimulation. According to the concentrations which reduced the stimulation-induced overflow by 20% (EC20 pre), the rank order of potency was: adrenaline greater than oxymetazoline greater than tramazoline greater than alpha-methylnoradrenaline greater than noradrenaline greater than naphazoline greater than phenylephrine greater than methoxamine. 10(-5) M phentolamine shifted the presynaptic dose-response curves for moradrenaline and oxymethazoline to the right. 3. The ratio EC20 pre/EC20 post was calculated for each agonist as an index of its relative post- and presynaptic potency. According to the ratios, the agonists were arbitrarily classified into three groups. Group 1 (ratio about 30: preferentially postsynaptic agonists) comprised methoxamine and phenylephrine; group 2 (ratio near 1; similar pre- and postsynaptic potencies) comprised noradrenaline, adrenaline and naphazoline; group 3 (ratio below 0.2; preferentially presynaptic agonists) comprised oxymetazoline, alpha-methylnoradrenaline and tramazoline (as well as clonidine). 4. Preferentially presynaptic and preferentially postsynaptic agonists had opposite effects on the basoconstrictor response to nerve stimulation. Methoxamine and phenylephrine either did not change or enhanced, but never reduced, the response. In contrast, oxymetazoline, alpha-methylnoradrenaline and tramazoline at low concentrations selectively inhibited the response to stimulation at low frequency (0.25-2Hz). 5. It is concluded that alpha-adrenoceptor agonists vary widely in their relative pre- and postsynaptic potencies, possibly because of structural differences between pre- and postsynaptic alpha-receptors. Pre- and postsynaptic components contribute to their overll postsynaptic effec in actively transmitting synapses. The preferential activation of presynaptic alpha-receptors results in alpha-adrenergic inhibition of synaptic transmission.

Adrenergic alpha-Agonists↗
PubMed1978

Differences between agonist and antagonist binding following beta-adrenergic receptor desensitization.

The specific beta-adrenergic agonist radioligand (+/-)-[3H]hydroxybenzylisoproterenol ([3H]HBI) was used to investigate alterations in the beta-adrenergic receptors of frog erythrocytes occurring during the process of agonist-induced, receptor-specific desensitization. There was close agreement between the percentage fall in [3H]HBI binding and that in catecholamine-stimulated adenylate cyclase activity following periods of preincubation of up to 7 h with 0.1 mM (-)-isoproterenol. Desensitization was maximal by 5 h, resulting in a 69% reduction in [3H]HBI binding and a 67% reduction in isoproterenol-stimulated adenylate cyclase activity. In contrast, binding of the beta-adrenergic antagonist (-)-[3H]dihydroalprenolol was significantly less affected by desensitization (p is less than 0.05 at 2 1/2, 5, and 7 h), showing a maximum reduction in binding of only 35% in these experiments. The consistent close agreement of reduction in agonist binding with that in hormone-stimulated adenylate cyclase activity, together with the significant difference observed between agonist and antagonist binding, implies that an alteration occurs during desensitization which preferentially interferes with agonist binding, while antagonist binding is less affected. The locus of this agonist-specific alteration may be the receptor binding site or a site involved in receptor-enzyme coupling. Agonist binding studies may now be used to assess more completely the desensitized state of beta-adrenergic receptors in systems in which marked desensitization of beta-adrenergic responses is associated with little or no reduction in antagonist binding.

Adenylyl Cyclases↗
PubMed1979

Studies on histamine H2 receptors coupled to cardiac adenylate cyclase. Effects of guanylnucleotides and structural requirements for agonist activity.

In particulate preparations from guinea-pig ventricle, histamine in the concentration range 10(-6)--10(-3) M caused a 3--5fold stimulation of adenylate cyclase activity which was dependent on the presence of GTP. The effects of fourteen analogs of histamine were examined on this cyclase preparation. Five of the compounds studied proved to be partial agonists relative to histamine while nine others had essentially the same intrinsic activity as histamine. The intrinsic activities of the partial agonists were increased by GppNHp to the extent that dimaprit, which was a partial agonist in the presence of GTP, became a full agonist in the presence of GppNHp. The relative potencies of the full agonists as activators of the cyclase were found to correlate with the relative potencies on physiologically defined H2 receptor systems. Activation of the cyclase by histamine, as well as by several of the agonist analogs, including dimaprit and tolazoline, was completely blocked by the H2 antagonist cimetidine, but was not affected by pharmacologically relevant concentrations of the H1 antagonist mepyramine, the beta-blocker alprenolol, or the alpha-blocker phentolamine. The results suggest that all the agonists studied probably interact with a common H2 receptor site on the cardiac muscle cell leading to activation of adenylate cyclase. The accompanying increase in cyclic AMP is presumably responsible for the chronotropic and inotropic effects of histamine and related compounds on cardiac muscle.

Adenylyl Cyclases↗
PubMed2026

Genome-wide chromatin profiling reveals a nonlimiting role for RXR in macrophage-like cells stimulated with multiple nuclear receptor agonists.

Retinoid X receptor (RXR) is an obligate heterodimerization partner for many nuclear receptors. In the absence of ligands, RXR occupies thousands of genomic regions, with its binding landscape predominantly determined by cell identity. In the presence of agonists of RXR or its partners, RXR occupancy is changed at a subset of binding regions. The characteristics of these ligand-responsive binding regions remain largely unexplored. We used ChIP-seq to profile RXR occupancy in PMA-differentiated THP-1 cells treated with agonists of RXR or partner receptors, including RARα, VDR, PPARδ, PPARγ, LXRs, and TR, or a "cocktail" containing multiple agonists. The RXR agonist LG268 produced a stronger increase in RXR occupancy than any of the six partner-receptor agonists or their combination. The relevance of ligand-induced RXR peaks was confirmed by the analyses of motif enrichment and RXR occupancy at regulatory elements of target genes. RXR binding was investigated in more detail in cells treated with the VDR agonist, calcitriol. Calcitriol markedly enhanced VDR binding, but the corresponding increase in RXR occupancy was less pronounced. We found that both ligand-induced and unresponsive RXR peaks were involved in gene regulation, and only a small subset (∼3%) of calcitriol-regulated genes exhibited decreases in both RXR binding and mRNA levels in response to combined agonist treatment. These results support a model in which RXR functions as a nonlimiting module in a macrophage-like cell type, and interference between pathways is minimally attributable to RXR sequestration.

Humans↗