2,4-Diaminopyrimidine Derivatives as Potent Growth Hormone Secretagogue Receptor Antagonists

Serby, Michael D.; Zhao, Hongyu; Szczepankiewicz, Bruce G.; Kosogof, Christi; Xin, Zhili; Liu, Bo; Liu, Mei; Nelson, Lawrence J.; Kaszubska, Wiweka; Falls, Hugh D.; Schaefer, Verlyn G.; Bush, Eugene N.; Shapiro, Robin; Droz, Brian A.; Knourek-Segel, Victoria; Fey, Thomas A.; Brune, Michael E.; Beno, David W. A.; Turner, Theresa M; Collins, Christine A.; Jacobson, Peer B.; Sham, Hing L.; Liu, Gang

doi:10.1021/jm0510934

Cited by 45 publications

(49 citation statements)

References 34 publications

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“…If the increase in seizure threshold is due to the loss of constitutively active GHSR receptors, rather than a developmental consequence of the absence of the receptor throughout the life of the GHSR -/-mice, then it may be possible to mimic the effects by inactivating the GHSR. We started investigating the pharmacological properties of the presumed GHSR antagonist A778193, which has a nanomolar affinity for the GHSR [35]. Using HEK293 cells expressing the cloned hGHSR, we found that A778193 in fact acts as a potent inverse agonist with a pIC 50 of 6.13±0.22 (n03) (Fig.…”

Section: Ghsr -/-Mice Are Less Susceptible To Limbic Seizures With Sementioning

confidence: 99%

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

et al. 2012

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Ghrelin is a pleiotropic neuropeptide that has been recently implicated in epilepsy. Animal studies performed to date indicate that ghrelin has anticonvulsant properties; however, its mechanism of anticonvulsant action is unknown. Here we show that the anticonvulsant effects of ghrelin are mediated via the growth hormone secretagogue receptor (GHSR). To our surprise, however, we found that the GHSR knockout mice had a higher seizure threshold than their wild-type littermates when treated with pilocarpine. Using both in vivo and in vitro models, we further discovered that inverse agonism and desensitization/internalization of the GHSR attenuate limbic seizures in rats and epileptiform activity in hippocampal slices. This constitutes a novel mechanism of anticonvulsant action, whereby an endogenous agonist reduces the activity of a constitutively active receptor.

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Section: Ghsr -/-Mice Are Less Susceptible To Limbic Seizures With Sementioning

confidence: 99%

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

et al. 2012

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“…In present study 2, 4-diaminopyrimidine derivatives (Table I) have been taken from the literature report [16] along with their antagonistic activity. The activity was expressed as the logarithm of the inverse of inhibitory concentration, pIC 50 , where IC 50 represents the molar concentration, required to bring out 50% inhibition of GHS-R. Two different approaches, namely the non-parametric and the parametric, have been used to develop the important QSARs of titled compounds.…”

Section: Data Setmentioning

confidence: 99%

“…However, these compounds did not exhibit an effect when tested in in vivo animal models. More recently, a synthetic study was performed [16] on the derivatives of 2,4-diaminopyrimidine and to identify them as effective GHS-R antagonists. These compounds were first run in the GHS-R binding assays and were further investigated in an intracellular Ca +2 flux activity assay.…”

Section: Introductionmentioning

confidence: 99%

Modeling of the growth hormone secretagogue receptor antagonistic activity using chemometric tools

Sharma¹,

Sharma²,

Pilania³

et al. 2009

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Through its action on growth hormone secretagogue receptor type 1a, ghrelin exerts a variety of metabolic functions including stimulation of growth hormone release, stimulation of appetite and weight gain, and suppression of insulin secretion in rodents and humans (Nakazato et al, 2001;Wren et al, 2001;Dezaki et al, 2008;Cardona Cano et al, 2012;Heppner et al, 2012). Thus, antagonizing growth hormone secretagogue receptor (GHSR)-1a with small molecule antagonists or inverse agonists is anticipated to improve glucose homeostasis and insulin sensitivity, while eliciting beneficial effects on body weight (Serby et al, 2006;Esler et al, 2007;Rudolph et al, 2007;Soares et al, 2008;Costantino and Barlocco, 2009).…”

Section: Introductionmentioning

confidence: 99%

Reactive Metabolite Trapping Studies on Imidazo- and 2-Methylimidazo[2,1-b]thiazole-Based Inverse Agonists of the Ghrelin Receptor

et al. 2013

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The current study examined the bioactivation potential of ghrelin receptor inverse agonists, 1-{2-[2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl]-2,7-diazaspiro[3.5]nonan-7-yl}-2-(imidazo[2,1-b]thiazol-6-yl)ethanone (1) and 1-{2-[2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl]-2,7-diazaspiro[3.5]nonan-7-yl}-2-(2-methylimidazo[2,1-b]thiazol-6-yl) ethanone (2), containing a fused imidazo[2,1-b]thiazole motif in the core structure. Both compounds underwent oxidative metabolism in NADPH-and glutathione-supplemented human liver microsomes to yield glutathione conjugates, which was consistent with their bioactivation to reactive species. Mass spectral fragmentation and NMR analysis indicated that the site of attachment of the glutathionyl moiety in the thiol conjugates was on the thiazole ring within the bicycle. Two glutathione conjugates were discerned with the imidazo[2,1-b]thiazole derivative 1. One adduct was derived from the Michael addition of glutathione to a putative S-oxide metabolite of 1, whereas, the second adduct was formed via the reaction of a second glutathione molecule with the initial glutathione-S-oxide adduct. In the case of the 2-methylimidazo[2,1-b]thiazole analog 2, glutathione conjugation occurred via an oxidative desulfation mechanism, possibly involving thiazole ring epoxidation as the rate-limiting step. Additional insights into the mechanism were obtained via 18 O exchange and trapping studies with potassium cyanide. The mechanistic insights into the bioactivation pathways of 1 and 2 allowed the deployment of a rational chemical intervention strategy that involved replacement of the thiazole ring with a 1,2,4-thiadiazole group to yield 2-,4]thiadiazol-6-yl)ethanone (3). These structural changes not only abrogated the bioactivation liability but also retained the attractive pharmacological attributes of the prototype agents.

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2,4-Diaminopyrimidine Derivatives as Potent Growth Hormone Secretagogue Receptor Antagonists

Cited by 45 publications

References 34 publications

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

Modeling of the growth hormone secretagogue receptor antagonistic activity using chemometric tools

Reactive Metabolite Trapping Studies on Imidazo- and 2-Methylimidazo[2,1-b]thiazole-Based Inverse Agonists of the Ghrelin Receptor

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