Development of potent gastrin-releasing peptide antagonists having a D-Pro-psi(CH2NH)-Phe-NH2 C terminus.

Leban, Johann; Kull, Frederick C.; Landavazo, Antonio; Stockstill, Beth; McDermed, John D.

doi:10.1073/pnas.90.5.1922

Cited by 26 publications

(35 citation statements)

References 31 publications

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“…With the elucidation of the structure of gastrin, several peptide analogs of gastrin were synthesized, which could theoretically competitively inhibit gastrin-stimulated acid secretion [15]. However, these were not effective, and a more potent series of non-peptide compounds have been developed subsequently, though they are still not in clinical use [16].…”

Section: Gastrin Receptor Antagonistsmentioning

confidence: 99%

Molecular mechanisms in therapy of acid-related diseases

Shin

Vagin

Munson

et al. 2007

Cell. Mol. Life Sci.

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Inhibition of gastric acid secretion is the mainstay of the treatment of gastroesophageal reflux disease and peptic ulceration; therapies to inhibit acid are among the best-selling drugs worldwide. Highly effective agents targeting the histamine H2 receptor were first identified in the 1970s. These were followed by the development of irreversible inhibitors of the parietal cell hydrogenpotassium ATPase (the proton pump inhibitors) that inhibit acid secretion much more effectively. Reviewed here are the chemistry, biological targets and pharmacology of these drugs, with reference to their current and evolving clinical utilities. Future directions in the development of acid inhibitory drugs include modifications of current agents and the emergence of a novel class of agents, the acid pump antagonists.

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Section: Gastrin Receptor Antagonistsmentioning

confidence: 99%

Molecular mechanisms in therapy of acid-related diseases

Shin

Vagin

Munson

et al. 2007

Cell. Mol. Life Sci.

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“…Subsequently, a particularly potent group of pseudopeptide antagonists, having a D-Pro-(CH 2 NH)-Phe-NH 2 moiety at the COOH terminus of GRP, were described (Leban et al, 1993). One of the most potent and widely used analogs in this series is (3-PhPr)-His,Trp,Ala,Val,D-Ala,His,D-Pro-(CH 2 NH)-Phe-NH 2 (BW2258U89) [(K i 0.001 nM murine BB 2 ) (Leban et al, 1993); 0.7 nM rat BB 2 , and 10 nM human BB 2 (Moody et al, 1996a)]. BW2258U89 has Ͼ10,000 fold selectivity for the rat BB 2 over the rat BB 1 receptor Katsuno et al, 1999) (Table 2).…”

Section: Bb 2 Receptor Expressionmentioning

confidence: 99%

“…A number of the shortened D-Phe substituted [13][14]Bn 6 -14 analogs are Ͼ100-fold more selective for the BB 2 over the BB 1 receptor (von Schrenck et al, 1990;Mantey et al, 1997;Katsuno et al, 1999). Subsequently, a particularly potent group of pseudopeptide antagonists, having a D-Pro-(CH 2 NH)-Phe-NH 2 moiety at the COOH terminus of GRP, were described (Leban et al, 1993). One of the most potent and widely used analogs in this series is (3-PhPr)-His,Trp,Ala,Val,D-Ala,His,D-Pro-(CH 2 NH)-Phe-NH 2 (BW2258U89) [(K i 0.001 nM murine BB 2 ) (Leban et al, 1993); 0.7 nM rat BB 2 , and 10 nM human BB 2 (Moody et al, 1996a)].…”

Section: Bb 2 Receptor Expressionmentioning

confidence: 99%

International Union of Pharmacology. LXVIII. Mammalian Bombesin Receptors: Nomenclature, Distribution, Pharmacology, Signaling, and Functions in Normal and Disease States

Jensen

Battey

Spindel³

et al. 2007

Pharmacol Rev

479

720

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“…However, each of these peptides was also found to have low affinities in the micromolar range for the hBRS-3. Fourth, six different classes of GRP receptor (21,24) or NMB receptor (22) antagonists have been described, some of which are highly selective. Representative members of each of these different classes of antagonists were examined, and none were found to interact with the hBRS-3 with affinity above the micromolar range.…”

Section: Brs-3 Receptor Pharmacologymentioning

confidence: 99%

Discovery of a High Affinity Radioligand for the Human Orphan Receptor, Bombesin Receptor Subtype 3, Which Demonstrates That It Has a Unique Pharmacology Compared with Other Mammalian Bombesin Receptors

Mantey¹,

Weber²,

Sainz³

et al. 1997

Journal of Biological Chemistry

157

290

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An orphan receptor discovered in 1993 was called bombesin receptor subtype 3 (BRS-3) because of 47-51% amino acid identity with bombesin (Bn) receptors. Its pharmacology is unknown, because no naturally occurring tissues have sufficient receptors to allow studies. ]Bn-(6 -14) bound to both cell lines with high affinity. Neither Bn nor 14 other naturally occurring Bn peptides bound to hBRS-3 with a K d <1000 nM. Twenty-six synthetic peptides that are high affinity agonists or antagonists at other bombesin receptors had an affinity >1000 nM. Guanosine 5-(␤,␥-imido)triphosphate inhibited binding to both cells due to a change in receptor affinity. These results demonstrate hBRS-3 has a unique pharmacology. It does not interact with high affinity with any known natural agonist or high affinity antagonist of the Bn receptor family, suggesting the natural ligand is either an undiscovered member of the Bn peptide family or an unrelated peptide. The availability of these cell lines and the hBRS-3 ligand should facilitate identification of the natural ligand for BRS-3, its pharmacology, and cell biology. We made two cell lines stably expressing the human BRS-3 (hBRS-3). hBRS-3 was overexpressed in the huRecently, an orphan receptor that is a member of the heptahelical superfamily of receptors was described in both human small cell lung cancer cells (1) and guinea pig uterus (2). Because this orphan receptor had a high degree of homology to mammalian bombesin receptors (i.e. 51-52% for the gastrinreleasing peptide receptor (GRP-R) 1 and 47% for the neuromedin B receptor (NMB-R) (1, 2)), it was named the BRS-3 for bombesin receptor subtype-3 in one study (1). Studies of the distribution of the receptor mRNA show that BRS-3 has a pattern of expression limited to rat secondary spermatocytes (1), guinea pig brain and pregnant uterus (2), and some tumor cell lines (various human small cell and non-small cell lung cancer cell lines (1), the human ductal breast cancer cell line T47D (3), and the human epidermal cancer cell line A431 (3)). However, the natural ligand that interacts with the BRS-3 is unknown, and its pharmacology is largely unknown because of the lack of a radioligand. In addition, little is known about the cellular basis of action of BRS-3 except that it is coupled to phospholipase C when expressed in Xenopus oocytes (1) or when transfected into Balb 3T3 cells (4). The ability to elucidate the pharmacology of the BRS-3 is not only limited by the lack of a radioligand but also by the lack of a cell containing native BRS-3 receptors in sufficient numbers to allow binding studies to identify a possible radioligand.To deal with this latter issue, in the present study we have used two different strategies to produce cell lines stably expressing the human BRS-3 (hBRS-3) receptor whose pharmacology and coupling will probably closely resemble that of the native hBRS-3. Furthermore, we have discovered a unique ligand that is a synthetic analogue of bombesin-(6 -14), which interacts with high affinity with the hBRS-3. With ...

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Development of potent gastrin-releasing peptide antagonists having a D-Pro-psi(CH2NH)-Phe-NH2 C terminus.

Cited by 26 publications

References 31 publications

Molecular mechanisms in therapy of acid-related diseases

Molecular mechanisms in therapy of acid-related diseases

International Union of Pharmacology. LXVIII. Mammalian Bombesin Receptors: Nomenclature, Distribution, Pharmacology, Signaling, and Functions in Normal and Disease States

Discovery of a High Affinity Radioligand for the Human Orphan Receptor, Bombesin Receptor Subtype 3, Which Demonstrates That It Has a Unique Pharmacology Compared with Other Mammalian Bombesin Receptors

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