Pharmacokinetics and Pharmacodynamics of MK‐5046, a Bombesin Receptor Subtype‐3 (BRS‐3) Agonist, in Healthy Patients

Reitman, Marc L.; Dishy, Victor; Moreau, Allison; Denney, William S.; Liu, Chengcheng; Kraft, Walter K.; Mejia, Alex; Matson, Mark; Stoch, S. Aubrey; Wagner, John A.; Lai, Eseng

doi:10.1177/0091270011419854

Cited by 34 publications

(43 citation statements)

References 36 publications

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“…As noted, the effects of the BRS-3 system on Tb are likely secondary to its primary role in energy homeostasis. This makes the concern that BRS-3 agonists will produce clinical hyperthermia unlikely, and is consistent with the lack of observed Tb changes in men treated with MK-5046 (30). The realization that adult humans can and do expend energy via BAT activation has brought attention to BAT (24) and highlighted the potential for drugs that activate BAT as a treatment for obesity (36).…”

Section: E684 Brs-3 Regulation Of Body Temperature Terizing Brs3mentioning

confidence: 61%

Regulation of body temperature and brown adipose tissue thermogenesis by bombesin receptor subtype-3

Lateef

Abreu-Vieira

Xiao

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Bombesin receptor subtype-3 (BRS-3) regulates energy homeostasis, with Brs3 knockout (Brs3 Ϫ/y ) mice being hypometabolic, hypothermic, and hyperphagic and developing obesity. We now report that the reduced body temperature is more readily detected if body temperature is analyzed as a function of physical activity level and light/dark phase. Physical activity level correlated best with body temperature 4 min later. The Brs3 Ϫ/y metabolic phenotype is not due to intrinsically impaired brown adipose tissue function or in the communication of sympathetic signals from the brain to brown adipose tissue, since Brs3 Ϫ/y mice have intact thermogenic responses to stress, acute cold exposure, and ␤3-adrenergic activation, and Brs3 Ϫ/y mice prefer a cooler environment. Treatment with the BRS-3 agonist MK-5046 increased brown adipose tissue temperature and body temperature in wild-type but not Brs3 Ϫ/y mice. Intrahypothalamic infusion of MK-5046 increased body temperature. These data indicate that the BRS-3 regulation of body temperature is via a central mechanism, upstream of sympathetic efferents. The reduced body temperature in Brs3 Ϫ/y mice is due to altered regulation of energy homeostasis affecting higher center regulation of body temperature, rather than an intrinsic defect in brown adipose tissue.bombesin receptor subtype-3; obesity; sympathetic nervous system; brown adipose tissue; thermoregulation; CL316243; MK-5046 OBESITY, AN IMBALANCE BETWEEN energy intake and energy expenditure, is associated with several comorbidities, including diabetes mellitus and cardiovascular disease. Current treatments for obesity are inadequate, stimulating research to better understand the physiology of energy homeostasis and to develop safe and effective pharmacologic treatments. The study of bombesin receptor subtype-3 (BRS-3) can advance both of these objectives.BRS-3 is a G protein-coupled receptor for which the natural ligand is unknown, and despite its name, BRS-3 has a low affinity for bombesin and related natural peptides (7,17,21). In addition to other locations, BRS-3 is present in the central nervous system, including the hypothalamus and caudal brainstem (10,16,26,37), regions involved in the regulation of feeding, energy expenditure, and body weight (32). Genetic and pharmacologic studies demonstrate a role for BRS-3 in energy homeostasis. Brs3 knockout (Brs3 Ϫ/y ) mice exhibit hyperphagia, reduced metabolic rate, and obesity (18, 27), and pharmacological blockade of BRS-3 in rats increases food intake and body weight (10). Conversely, BRS-3 agonists reduced food intake, increased metabolic rate and body temperature (Tb), and reduced body weight in mice, rats, and dogs (10,11,22).Currently, the mechanisms underlying Tb regulation by BRS-3 are unclear. Brown adipose tissue (BAT) is the major site of facultative thermogenesis, dissipating chemical energy via uncoupling protein 1 (UCP1), thereby generating heat and maintaining Tb (2). BAT activity is regulated by sympathetic neural input, with upstream regulation from hypot...

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Section: E684 Brs-3 Regulation Of Body Temperature Terizing Brs3mentioning

confidence: 61%

Regulation of body temperature and brown adipose tissue thermogenesis by bombesin receptor subtype-3

Lateef

Abreu-Vieira

Xiao

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Peptide #1 had a more rapid onset and shorter duration of action for each. This difference was not due to a difference in stability with the two agonists, as previous studies had demonstrated that each is stable under incubation conditions at 37°C for at least 1 hour (Mantey et al, 1997;Sebhat et al, 2011;Reitman et al, 2012). Compared with previous studies that investigated the kinetics/duration of action of peptide and nonpeptide agonists, our results are similar to those with the CCK1-receptor nonpeptide agonist SR146131 (Bignon et al, 1999;Schaeffer et al, 2000), where the nonpeptide had a more prolonged duration of the action in stimulating [Ca 21 ] i when it was compared with an equally effective dose of the natural agonist CCK-8S.…”

Section: Discussionmentioning

confidence: 78%

“…Recent studies have reported that the nonpeptide MK-5046 [(2S)-1,1,1-trifluoro-2-[4-(1H-pyrazol-1-yl)phenyl]-3-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)propan-2-ol] is an orally active, potent, and selective BRS-3 agonist (Sebhat et al, 2011;Guan et al, 2011;Reitman et al, 2012), with activity in mice, rats, dogs , and humans (Reitman et al, 2012). Furthermore, recently a selective peptide antagonist Bantag-1 [Boc-Phe-His-4-amino-5-cyclohexyl-2,4,5-trideoxypentonyl-Leu-(3-dimethylamino) benzylamide N-methylammonium trifluoroacetate] also has been reported (Guan et al, 2010;Feng et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Comparative Pharmacology of Bombesin Receptor Subtype-3, Nonpeptide Agonist MK-5046, a Universal Peptide Agonist, and Peptide Antagonist Bantag-1 for Human Bombesin Receptors

Moreno

Mantey

Nuche-Berenguer

et al. 2013

J Pharmacol Exp Ther

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Bombesin-receptor-subtype-3 (BRS-3) is an orphan G-proteincoupled receptor of the bombesin (Bn) family whose natural ligand is unknown and which does not bind any natural Bnpeptide with high affinity. It is present in the central nervous system, peripheral tissues, and tumors; however, its role in normal physiology/pathophysiology is largely unknown because of the lack of selective ligands. Recently, MK-5046and Bantag-1 [Boc-Phe-His-4-amino-5-cyclohexyl-2,4,5-trideoxypentonyl-Leu-(3-dimethylamino) benzylamide N-methylammonium trifluoroacetate], a nonpeptide agonist and a peptide antagonist, respectively, for BRS-3 have been described, but there have been limited studies on their pharmacology. We studied MK-5046 and Bantag-1 interactions with human Bn-receptors-human bombesin receptor subtype-3 (hBRS-3), gastrin-releasing peptide receptor (GRP-R), and neuromedin B receptor (NMB-R)-and compared them with the nonselective, peptide-agonist [D-Tyr6,bAla11,Phe13, Nle14]Bn-(6-14) (peptide #1). Receptor activation was detected by activation of phospholipase C (PLC), mitogen-activated protein kinase (MAPK), focal adhesion kinase (FAK), paxillin, and Akt. In hBRS-3 cells, the relative affinities were Bantag-1 (1.3 nM) . peptide #1 (2 nM) . MK-5046 (37-160 nM) . GRP, NMB (.10 mM), and the binding-dose-inhibition curves were broad (.4 logs), with Hill coefficients differing significantly from unity. Curve-fitting demonstrated high-affinity (MK-5046, K i 5 0.08 nM) and low-affinity (MK-5046, K i 5 11-29 nM) binding sites. For PLC activation in hBRS-3 cells, the relative potencies were MK-5046 (0.02 nM) . peptide #1 (6 nM) . GRP, NMB, Bantag-1 (.10 mM), and MK-5046 had a biphasic dose response, whereas peptide #1 was monophasic. Bantag-1 was a specific hBRS-3-antagonist. In hBRS-3 cells, MK-5046 was a full agonist for activation of MAPK, FAK, Akt, and paxillin; however, it was a partial agonist for phospholipase A 2 (PLA 2 ) activation. The kinetics of activation/ duration of action for PLC/MAPK activation of MK-5046 and peptide #1 differed, with peptide #1 causing more rapid stimulation; however, MK-5046 had more prolonged activity. Our study finds that MK-5046 and Bantag-1 have high affinity/selectivity for hBRS-3. The nonpeptide MK-5046 and peptide #1 agonists differ markedly in their receptor coupling, ability to activate different signaling cascades, and kinetics/duration of action. These results show that their hBRS-3 receptor activation is not always concordant and could lead to markedly different cellular responses.

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“…It is unknown if this hypertensive effect of MK-5046 would be more pronounced in elderly or patients with diminished baroreflex function. The adverse effects of BRS-3 agonists attenuate with continued dosing (14,37,46). We have not investigated attenuation in mice, making this an important question for future studies.…”

Section: Discussionmentioning

confidence: 99%

“…One BRS-3 agonist, MK-5046, transiently increased blood pressure in rats, dogs, and humans (but has not been studied in mice) (15,46). A different BRS-3 agonist also increased blood pressure, while a third agonist reduced it, making it unclear if the blood pressure effects are mediated via BRS-3 (15).…”

Section: Mk-5046 a Bombesin-like Receptor 3 (Brs-3) Agonist Increasmentioning

confidence: 99%

Bombesin-like receptor 3 regulates blood pressure and heart rate via a central sympathetic mechanism

Lateef

Xiao

Brychta

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Lateef DM, Xiao C, Brychta RJ, Diedrich A, Schnermann J, Reitman ML. Bombesin-like receptor 3 regulates blood pressure and heart rate via a central sympathetic mechanism. Am J Physiol Heart Circ Physiol 310: H891-H898, 2016. First published January 22, 2016; doi:10.1152/ajpheart.00963.2015.-Bombesin-like receptor 3 (BRS-3) is an orphan G protein-coupled receptor that regulates energy expenditure, food intake, and body weight. We examined the effects of BRS-3 deletion and activation on blood pressure and heart rate. In free-living, telemetered Brs3 null mice the resting heart rate was 10% lower than wild-type controls, while the resting mean arterial pressure was unchanged. During physical activity, the heart rate and blood pressure increased more in Brs3 null mice, reaching a similar heart rate and higher mean arterial pressure than control mice. When sympathetic input was blocked with propranolol, the heart rate of Brs3 null mice was unchanged, while the heart rate in control mice was reduced to the level of the null mice. The intrinsic heart rate, measured after both sympathetic and parasympathetic blockade, was similar in Brs3 null and control mice. Intravenous infusion of the BRS-3 agonist MK-5046 increased mean arterial pressure and heart rate in wild-type but not in Brs3 null mice, and this increase was blocked by pretreatment with clonidine, a sympatholytic, centrally acting ␣ 2-adrenergic agonist. In anesthetized mice, hypothalamic infusion of MK-5046 also increased both mean arterial pressure and heart rate. Taken together, these data demonstrate that BRS-3 contributes to resting cardiac sympathetic tone, but is not required for activity-induced increases in heart rate and blood pressure. The data suggest that BRS-3 activation increases heart rate and blood pressure via a central sympathetic mechanism.bombesin-like receptor 3; blood pressure; heart rate; sympathetic nervous system; energy metabolism NEW & NOTEWORTHY MK-5046, a bombesin-like receptor 3 (BRS-3) agonist, increases heart rate and blood pressure via increased central sympathetic tone. Brs3 null mice have a reduced resting heart rate that increases disproportionately with physical activity. BRS-3 contributes to the central regulation of heart rate and blood pressure.OBESITY is strongly associated with cardiovascular risk factors, including hypertension (6). However, the mechanisms linking obesity and hypertension are not fully understood (7,44). A number of neuroendocrine systems controlling energy homeostasis also regulate blood pressure and heart rate, including leptin, the melanocortin system, and ghrelin (12, 36, 45, 48 -50). The genetic and pharmacological manipulations of these systems that reduce adiposity generally also increase blood pressure, which is undesirable in a treatment for obesity.Bombesin-like receptor 3 (BRS-3) is a G protein-coupled receptor for which the endogenous ligand is unidentified (4,21,29,33). Despite the name, BRS-3 has a low affinity for bombesin and the related molecules, neuromedin B and gastrin-releasing ...

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Pharmacokinetics and Pharmacodynamics of MK‐5046, a Bombesin Receptor Subtype‐3 (BRS‐3) Agonist, in Healthy Patients

Cited by 34 publications

References 36 publications

Regulation of body temperature and brown adipose tissue thermogenesis by bombesin receptor subtype-3

Regulation of body temperature and brown adipose tissue thermogenesis by bombesin receptor subtype-3

Comparative Pharmacology of Bombesin Receptor Subtype-3, Nonpeptide Agonist MK-5046, a Universal Peptide Agonist, and Peptide Antagonist Bantag-1 for Human Bombesin Receptors

Bombesin-like receptor 3 regulates blood pressure and heart rate via a central sympathetic mechanism

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