Peptide Mimetics of Thyrotropin-Releasing Hormone Based on a Cyclohexane Framework: Design, Synthesis, and Cognition-Enhancing Properties

Olson, Gary L.; Cheung, H.‐C.; Chiang, Elliot; Madison, Vincent; Sepinwall, Jerry; Vincent, George P.; Winokur, Andrew; Gary, Keith A.

doi:10.1021/jm00015a009

Cited by 60 publications

(27 citation statements)

References 10 publications

(22 reference statements)

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“…they did not exhibit endocrine activity. These studies, therefore, suggested that the conformation is the determinant of cognitive activity and that binding to the micromolar affinity binding site in rat brain slices is distinct from, and probably unrelated to, binding to TRH-R [29].…”

Section: Backbonementioning

confidence: 98%

“…Interestingly, although the presence of the specific basic, aromatic and steric properties of the imidazole side chain of the central histidine is regarded as a decisive factor in the binding of TRH to TRH-R1, and hence for the full thyrotropin releasing activity [28], the imidazole NH appears not to be essential for cognitive effects in the Morris water maze model as mentioned below [29].…”

Section: Histidinementioning

confidence: 99%

“…Further testing to evaluate their CNS activity would be of interest. In a separate study, Olson et al [29] designed analogs in which the peptide backbone was entirely replaced by a cyclohexane framework. These mimetics were potent and orally active in a behavioral model of cognition in which TRH is active.…”

Section: Backbonementioning

confidence: 99%

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Thyrotropin-Releasing Hormone Analogs

Colson

Gershengorn²

2006

MRMC

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Thyrotropin releasing hormone (TRH: pyroglutamic acid-histidine-prolineamide) regulates the activity of cells in the anterior pituitary and within the central and peripheral nervous systems. TRH, which has been the subject of much research over the past three decades, exerts its effects by acting through class A G-protein coupled receptors. The recent discovery of a second receptor subtype has generated an interest in the discovery of receptor subtype-selective TRH analogs. In this review, we describe advances in the development of TRH analogs and in the understanding of their mechanism of interaction with TRH receptors. We also describe the recent breakthrough in the identification of analogs that bind selectively at TRH-R2.

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Section: Backbonementioning

confidence: 98%

Section: Histidinementioning

confidence: 99%

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Thyrotropin-Releasing Hormone Analogs

Colson

Gershengorn²

2006

MRMC

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“…Subsequently, Bélanger and Dufresne implemented this proposal, describing non-peptidic mimic 1 (Figure 1) of the enkephalins (see 4 and 5 , Figure 2) that incorporated the bicyclo [2.2.2]-octane scaffold 8. Later, Olson and collaborators reported peptidomimetic 2 (Figure 1), which was designed to mimic the tripeptide thyroid releasing hormone (TRH) 9. Although 2 did not bind the endocrine receptor for which it was designed, it showed oral activity in animal models of cognitive dysfunction.…”

Section: Introductionmentioning

confidence: 99%

“…This was readily accomplished by replacing Lys 9 with Phe 9 ( 12 , Figure 10) or p -F-Phe 9 ( 13 ) 14d. These results, though pleasing, raised new questions.…”

Section: Introductionmentioning

confidence: 99%

The β-d-Glucose Scaffold as a β-Turn Mimetic

et al. 2009

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ConspectusActivity and selectivity are typically the first considerations when designing a drug. However, absorption, distribution, metabolism, excretion, and toxicity (ADMET) are equally important considerations. Peptides can provide a combination of potent binding and exquisite selectivity, as evidenced by their pervasive use as enzymes, hormones, and signaling agents within living systems. In particular, peptidic turn motifs are key elements of molecular recognition. They may be found at the exposed surfaces of globular proteins, where they are available for binding interactions with other peptides and small molecules.However, despite these advantages, peptides often make poor drugs. The amide backbone is subject to rapid enzymatic proteolysis, resulting in short half-lives. Furthermore, the ability of the amide backbone to hydrogen-bond with water restricts its ability to cross membranes and, consequentially, results in poor oral bioavailability. Accordingly, the development of nonpeptidic scaffolds that mimic peptidic turn motifs represents a promising means of converting peptidic agents into more drugable molecules. In this Account, we describe the design and synthesis of β-turn mimetics that use a β-D-glucose scaffold-the first use of a sugar scaffold for this purpose.Somatostatin (SRIF) is a small-protein (14 amino acid residues) human hormone; a shorter (6 amino acid residues) synthetic peptide, L-363-301, is a fully peptidal agonist. These two cyclic peptides share the β-turn motif comprising Phe 7 -Trp 8 -Lys 9 -Thr 10 (D-Trp 8 in the case of L-363,301), of which the Trp and Lys residues in the i+1 and i+2 positions respectively are critical for binding. In 1988, we initiated a program that tested and validated the then-novel proposition that the β-D-glucose scaffold can mimic the β-turn in L-363,301. The β-D-glucose scaffold proved to be an attractive mimic of a β-turn in part because it permits the convenient attachment of amino acid side chains via facile etherification reactions, rather than carboncarbon bond formations; it is also an inexpensive starting material with well-defined *To whom correspondence should be addressed. rfh@sas.upenn.edu. The unexpectedly high level of receptor affinity of selected analogs-as well as the fortuitous discovery that our peptidomimetics were active against several chemically distinct receptors -led us tohypothesize that these monosaccharides could access multiple potential binding modes. Our later studies of this sugar scaffold confirmed this property, which we termed pseudosymmetry, whereby multiple similar but non-identical motifs are displayed within a single analog. We propose the presence of pseudosymmetry to be an element of privilege and an advantage for lead discovery. NIH Public Access IntroductionPeptides play a fundamental role in biology. However, their use as therapeutics has been limited by their poor pharmacokinetic properties. 1 Peptides are subject to proteolysis, which results in short biological half-lives even after parenteral administration....

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Synthetic Uses of Tosylmethyl Isocyanide (TosMIC)

Leusen

2001

Organic Reactions

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TosMIC is the acronym for 4‐tolylsulfonylmethyl isocyanide or tosylmethyl isocyanide. It is the best‐known member of a series of about 25 sulfonyl‐substituted methyl isocyanides RSO 2 CH 2 NC collected in Chart 1 (p. 426). TosMIC is a multipurpose synthetic reagent. It is by far the most versatile synthon derived from methyl isocyanide. This chapter provides a complete account of the synthetic uses of TosMIC based on a literature search closed in January 1996, and supplemented with further data available to the authors. Also included are applications of some of the more important TosMIC homologs (TosCHRNC). TosMIC is the only commercially available sulfonylmethyl isocyanide. It is a stable, colorless, practically odorless solid, which can be stored at room temperature without decomposition. Four brief review papers on the chemistry of TosMIC have appeared, in 1980, 1987, 1993, and 1995. Several reviews on the chemistry of isocyanides in general are available. An effort has been made to make this chapter as complete as possible, in coverage both by tables and by references, with respect to the immediate objective: a survey of the “Synthetic Uses of TosMIC.” Emphasis is on the primary products derived from reactions of TosMIC and related isocyanides, with limited reference to the further utilization of these products. Thus, the next section gives a complete account of reductive cyanation, the conversion of aldehydes or ketones into cyanides with the use of TosMIC, but for obvious reasons synthetic applications of the product cyanides are not treated in this chapter. One of the subsequent sections describes the application of TosMIC to the synthesis of pyrroles, including 2,3‐divinylpyrroles, which are important precursors in a new synthesis of indoles. This latter transformation, made possible by the easy availability of the precursors through TosMIC chemistry, is afforded brief coverage. As a rule, reference to preliminary papers has been omitted when the same information is available from the corresponding full papers. The patent literature is covered highly selectively and is cited only when providing new and relevant information. Negative results of reactions are reported in the text or tables only when at least some relevant information is available with respect to the conditions of such unsuccessful attempts.

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Peptide Mimetics of Thyrotropin-Releasing Hormone Based on a Cyclohexane Framework: Design, Synthesis, and Cognition-Enhancing Properties

Cited by 60 publications

References 10 publications

Thyrotropin-Releasing Hormone Analogs

Thyrotropin-Releasing Hormone Analogs

The β-d-Glucose Scaffold as a β-Turn Mimetic

Synthetic Uses of Tosylmethyl Isocyanide (TosMIC)

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