Distinctive binding properties of the negative allosteric modulator, [ 3 H]SB269,652, at recombinant dopamine D 3  receptors

Fasciani, Irene; Pietrantoni, Ilaria; Rossi, Mario; Cour, Clotilde Mannoury la; Aloisi, Gabriella; Marampon, Francesco; Scarselli, Marco; Millan, Mark J.; Maggio, Roberto

doi:10.1016/j.ejphar.2017.12.002

Cited by 5 publications

(7 citation statements)

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“…24 AAPs are known to bind to various neurotransmitters. 25 However, the mechanisms underlying the metabolic side effects of AAPs are largely unknown, but speculation abounds. Several studies have advanced the view that the involvement of genes that encode histamine, α adrenergic and dopamine D 2 receptors are likely to be involved in metabolic changes.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Side Effects of Olanzapine in Patients With Psychotic Disorders in Oman: A Retrospective Cohort Study

et al. 2022

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We evaluated the impact of olanzapine on metabolic changes in patients with psychotic disorders. This was a retrospective cohort study involving patients prescribed olanzapine and attending Sultan Qaboos University Hospital (Muscat, Oman). Patients were followed up retrospectively from March 2006 until April 2021. Cardiovascular treatment targets were evaluated as per the 2019 European Society of Cardiology guidelines. We enrolled 253 patients (mean age: 40±17 years). Olanzapine monotherapy was associated with increased body weight (+8 kg; 95% confidence interval (CI): 6–9; P < .001), body mass index (+3 kg/m2; 95% CI: 2–4; P < .001), total cholesterol (+.4 mmol/L; 95% CI: .3–.5; P < .001), low-density lipoprotein cholesterol (LDL-C) (+.3 mmol/L; 95% CI: .1–.4; P < .001), fasting triglycerides (+.2 mmol/L; 95% CI: .1–.3; P<.001), fasting glucose (+.6 mmol/L; 95% CI: .4–.7; P< .001), HbA1c (+.3%; 95% CI: .2–.4; P < .001), systolic blood pressure (BP) (+9 mmHg; 95% CI: 6–12; P < .001) and diastolic BP (+4 mmHg; 95% CI: 2–6; P < .001) levels. Cardiovascular therapeutic goals were attained in 38% (n = 97), 61% (n = 154), 71% (n = 180), and 59% (n = 150) for LDL-C, non–high-density lipoprotein cholesterol, triglycerides, and BP, respectively. Olanzapine was associated with adverse metabolic changes. Therefore, many patients were not at their target cardiovascular treatment goals.

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Section: Discussionmentioning

confidence: 99%

Metabolic Side Effects of Olanzapine in Patients With Psychotic Disorders in Oman: A Retrospective Cohort Study

et al. 2022

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“…Kumar et al [21] synthesized and pharmacological characterization of novel trans-cyclopropylmethyl-linked bivalent ligands with dopamine D 3 receptor (D 3 R) allosteric interactions. Fasciani et al [55] suggested that SB269,652 behaves as a bitopic antagonist at unoccupied dopamine D 3 R, binding simultaneously to both orthosteric and allosteric sites, and as a pure negative allosteric modulator when receptors are occupied, and it can solely bind to an allosteric site. Notably, all bitopic ligands are allosteric, for example, MRS7395 and XAC488 are demonstrated to be competitive antagonists in nature.…”

Section: Discussionmentioning

confidence: 99%

Allosteric Antagonism of the A2A Adenosine Receptor by a Series of Bitopic Ligands

Gao

Toti

Campbell

et al. 2020

Cells

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Allosteric antagonism by bitopic ligands, as reported for many receptors, is a distinct modulatory mechanism. Although several bitopic A2A adenosine receptor (A2AAR) ligand classes were reported as pharmacological tools, their receptor binding and functional antagonism patterns, i.e., allosteric or competitive, were not well characterized. Therefore, here we systematically characterized A2AAR binding and functional antagonism of two distinct antagonist chemical classes. i.e., fluorescent conjugates of xanthine amine congener (XAC) and SCH442416. Bitopic ligands were potent, weak, competitive or allosteric, based on the combination of pharmacophore, linker and fluorophore. Among antagonists tested, XAC, XAC245, XAC488, SCH442416, MRS7352 showed Ki binding values consistent with KB values from functional antagonism. Interestingly, MRS7396, XAC-X-BY630 (XAC630) and 5-(N,N-hexamethylene)amiloride (HMA) were 9–100 times weaker in displacing fluorescent MRS7416 binding than radioligand binding. XAC245, XAC630, MRS7396, MRS7416 and MRS7322 behaved as allosteric A2AAR antagonists, whereas XAC488 and MRS7395 antagonized competitively. Schild analysis showed antagonism slopes of 0.42 and 0.47 for MRS7396 and XAC630, respectively. Allosteric antagonists HMA and MRS7396 were more potent in displacing [3H]ZM241385 binding than MRS7416 binding. Sodium site D52N mutation increased and decreased affinity of HMA and MRS7396, respectively, suggesting possible preference for different A2AAR conformations. The allosteric binding properties of some bitopic ligands were rationalized and analyzed using the Hall two-state allosteric model. Thus, fluorophore tethering to an orthosteric ligand is not neutral pharmacologically and may confer unexpected properties to the conjugate.

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“…(a) Receptor selectivity—While orthosteric sites of GPCRs that bind the same or similar endogenous ligands are highly conserved due to evolutionary pressure, allosteric sites are less conserved, allowing for the accommodation of highly selective allosteric modulators. For instance, the negative allosteric modulator SB269652 is highly selective for D 3 receptor with 100–1000-fold less affinity for nearly all the other amine receptors [ 38 ].…”

Section: Allosteric Modulation Of Gpcrs and Influence On Receptor mentioning

confidence: 99%

“…SB269652 was originally synthesized by SmithKline Beecham in the effort to find new selective dopamine D 3 receptor antagonists [ 125 , 126 ]. Therefore, the radiolabeled [ 3 H]SB269652 shows a high binding affinity and selectivity for the dopamine D 3 receptor [ 38 ].…”

Section: Sb269652—a Prototypical Negative Allosteric Modulator Of mentioning

confidence: 99%

“…The 1H-indole-2-carboxamide moiety behaved as a pure allosteric drug at D 2 receptors, even though its affinity and negative cooperativity were weaker than SB269652. This molecule had similar affinity and negative allosteric effects for D 3 dopamine receptors compared to the D 2 receptors, which strongly suggested that the difference in affinity between D 2 and D 3 receptors depends on the binding of the 7CN-THIQ moiety to the orthosteric site of the two receptors [ 38 , 79 ]. Furthermore, Mistry et al (2015) [ 83 ] confirmed that the residues valine 91 and glutamic acid 95 of D 2 receptor were crucial for maintaining the allosteric properties of the 1H-indole-2-carboxamide derivative.…”

Section: Sb269652—a Prototypical Negative Allosteric Modulator Of mentioning

confidence: 99%

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Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics

et al. 2020

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Schizophrenia was first described by Emil Krapelin in the 19th century as one of the major mental illnesses causing disability worldwide. Since the introduction of chlorpromazine in 1952, strategies aimed at modifying the activity of dopamine receptors have played a major role for the treatment of schizophrenia. The introduction of atypical antipsychotics with clozapine broadened the range of potential targets for the treatment of this psychiatric disease, as they also modify the activity of the serotoninergic receptors. Interestingly, all marketed drugs for schizophrenia bind to the orthosteric binding pocket of the receptor as competitive antagonists or partial agonists. In recent years, a strong effort to develop allosteric modulators as potential therapeutic agents for schizophrenia was made, mainly for the several advantages in their use. In particular, the allosteric binding sites are topographically distinct from the orthosteric pockets, and thus drugs targeting these sites have a higher degree of receptor subunit specificity. Moreover, “pure” allosteric modulators maintain the temporal and spatial fidelity of native orthosteric ligand. Furthermore, allosteric modulators have a “ceiling effect”, and their modulatory effect is saturated above certain concentrations. In this review, we summarize the progresses made in the identification of allosteric drugs for dopamine and serotonin receptors, which could lead to a new generation of atypical antipsychotics with a better profile, especially in terms of reduced side effects.

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Distinctive binding properties of the negative allosteric modulator, [ 3 H]SB269,652, at recombinant dopamine D 3 receptors

Cited by 5 publications

References 46 publications

Metabolic Side Effects of Olanzapine in Patients With Psychotic Disorders in Oman: A Retrospective Cohort Study

Metabolic Side Effects of Olanzapine in Patients With Psychotic Disorders in Oman: A Retrospective Cohort Study

Allosteric Antagonism of the A2A Adenosine Receptor by a Series of Bitopic Ligands

Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics

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