Gary L. Olson

Provid Pharmaceuticals (United States)

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Wafik S. El‐Deiry

Brown University

Jessica Wagner

St. Jude Children's Research Hospital

Joshua E. Allen

Chimerix (United States)

David Bolin

King Abdullah University of Science and Technology

Bhaskara Rao Nallaganchu

Provid Pharmaceuticals (United States)

H.‐C. CHEUNG

La Roche College

Martin Stogniew

Oncoceutics (United States)

Robert M. Campbell

Queensland Children’s Hospital

C. Leah B. Kline

Fox Chase Cancer Center

Ramakanth Sarabu

Biocon (India)

Cooperative Institutions

La Roche College

Roche (Switzerland)

University of Pennsylvania

Merck & Co., Inc., Rahway, NJ, USA (United States)

Harvard University

Pfizer (United States)

GlaxoSmithKline (United States)

United States Military Academy

The University of Texas MD Anderson Cancer Center

Northwestern University

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ChemInform Abstract: DOPAMINE RECEPTOR MODEL AND ITS APPLICATION IN THE DESIGN OF A NEW CLASS OF RIGID PYRROLO(2,3‐G)ISOQUINOLINE ANTIPSYCHOTICS

Chemischer Informationsdienst (1982)

Gary L. Olson H.‐C. CHEUNG Kevin Morgan J. F. BLOUNT L. Todaro

Abstract Aus dem entsprechenden Ethylamin erhält man mit Chlorameisensäureethylester das Carbamat (Ia), dessen Reduktion mit Natrium‐dihydro‐bis‐(2‐methoxy‐ethoxy)‐aluminat in 83%iger Gesamtausbeute zum Methylamin (Ib) führt.

Isoquinoline

10.1002/chin.198205235

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Structure activity of C‐terminal modified analogs of Ac‐CCK‐7

International journal of peptide & protein research (1992)

Jefferson Tilley Waleed Danho S.-J. Shiuey I. D. KULESHA Ramakanth Sarabu

Previous work indicates that both the C ‐terminal phenylalanine amide and the tryptophan moieties of chole‐cystokinin (CCK) are critical pharmacophores for interaction with either the A or B receptor subtypes. We have examined a series of analogs of Ac‐CCK‐7 [Ac‐Tyr(SO 3 H)‐Met‐Gly‐Trp‐Met‐Asp‐Phe 33 ‐NH 2 ] (2) in which the phenyl ring of the C ‐terminal Phe‐NH 2 has been modified. Compounds were assessed in binding assays using homogenated rat pancreatic membranes and bovine striatum as the source of CCK‐A and CCK‐B receptors respectively and for anorectic activity after intraperitoneal administration to rats. Substitution of a number of cycloalkyi or bicyclic aryl moieties for the phenyl ring of phenylalanine 33 including cyclopentyl (20), cyclohexyl (21), cyclooctyl (23), 2‐(5,6,7,8‐tetrahydro)naphthyl (26), 2‐naphthyl (27), and 1‐naphthyl (29) led to analogs with 10–70 times the anorectic potency of 2. The anorectic activity of 21 was blocked by the specific CCK‐A receptor antagonist MK‐329. Other bulky aliphatic groups in place of the phenylalanine 33 aromatic ring such as isopropyl, 2‐adamantyl and cyclohexylmethyl gave derivatives similar to 2 in potency. While most of the new compounds were comparable to CCK in binding assays, 23, 26, 27 and 29 were exceptionally potent with IC 50 s 10 ‐11 ‐10 ‐14 M in the pancreas. Compounds 23 and 29 were further evaluated for their ability to stimulate amylase secretion and found to have potencies similar to that of CCK. The dissociation between potency in the binding and amylase secretion assays suggests that they may interact with a high affinity binding site which is not coupled to amylase secretion. We conclude that CCK receptors possess a generous hydrophobic pocket capable of accommodating large alkyl groups in place of the side chain of phenylalanine 33 and that the pharmacological profile of CCK analogs can be tailored by appropriate exploitation of this finding.

10.1111/j.1399-3011.1992.tb01592.x

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Citations (29)

Nonenzymic, biogenetic-like cyclization of a tetraenic acetal to produce the D-homosteroid nucleus

Journal of the American Chemical Society (1974)

William S. Johnson K. Wiedhaup Stephen F. Brady Gary L. Olson

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNonenzymic, biogenetic-like cyclization of a tetraenic acetal to produce the D-homosteroid nucleusWilliam S. Johnson, Koenraad Wiedhaup, Stephen F. Brady, and Gary L. OlsonCite this: J. Am. Chem. Soc. 1974, 96, 12, 3979–3984Publication Date (Print):June 1, 1974Publication History Published online1 May 2002Published inissue 1 June 1974https://pubs.acs.org/doi/10.1021/ja00819a041https://doi.org/10.1021/ja00819a041research-articleACS PublicationsRequest reuse permissionsArticle Views204Altmetric-Citations27LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

10.1021/ja00819a041

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ChemInform Abstract: Peptide Mimetics of Thyrotropin‐Releasing Hormone Based on a Cyclohexane Framework: Design, Synthesis, and Cognition‐Enhancing Properties.

ChemInform (1995)

Gary L. Olson H.‐C. CHEUNG Elliot Chiang Vincent Madison Jerry Sepinwall

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

10.1002/chin.199547242

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CCDC 2183723: Experimental Crystal Structure Determination

The Cambridge Structural Database (2022)

Jessica Wagner C. Leah B. Kline Richard S. Pottorf Bhaskara Rao Nallaganchu Gary L. Olson

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

10.5517/ccdc.csd.cc2c9bpq

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Correction: Discovery and clinical introduction of first-in-class imipridone ONC201

Oncotarget (2021)

Joshua E. Allen C. Leah B. Kline Varun V. Prabhu Jessica Wagner Jo Ishizawa

[This corrects the article DOI: 10.18632/oncotarget.11814.].

10.18632/oncotarget.28012

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Conformationally Defined Pyrroloisoquinoline Antipsychotics

ACS symposium series (1983)

Gary L. Olson H.‐C. CHEUNG Elizabeth Chiang Léo Berger

The pyrrolo- and cycloalka [4,5] pyrrolo [2,3-g] isoquinoline ring systems (1) were designed on the basis of a hypothetical model of the interaction of antipsychotic drugs with the dopamine receptor. The prototype (1a)(2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g] isoquinolin-4-one) (Ro 22-1319) is a potent, selective D-2 dopamine receptor antagonist which exhibits potent antipsychotic-like activity in animal tests and is being evaluated clinically. A series of analogs has been synthesized to probe the effects of substituents and ring size on pharmacological activity and receptor binding. Introducing bulky groups in the 2- and 3-positions, or increasing ring size in the cycloalka analogs diminishes activity and reveals a steric barrier near the 2-position. A wide range of substituents on the basic nitrogen are consistent with pharmacological activity, but only compounds having lipophilic substituents are proportionally potent in 3H-spiroperidol binding. The results suggest that interactions of the nitrogen substituent with the auxiliary binding site identified in the model modulates the activity between D-1 and D-2 dopamine receptors.

Isoquinoline

10.1021/bk-1983-0224.ch011

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Disruption of Protein Kinase A Localization Using a Trans-activator of Transcription (TAT)-conjugated A-kinase-anchoring Peptide Reduces Cardiac Function

Journal of Biological Chemistry (2010)

Hemal H. Patel Lora Hamuro Byeong Jo Chun Yoshitaka Kawaraguchi Alexander Quick

Localization of protein kinase A (PKA) via A-kinase-anchoring proteins (AKAPs) is important for cAMP responsiveness in many cellular systems, and evidence suggests that AKAPs play an important role in cardiac signaling. To test the importance of AKAP-mediated targeting of PKA on cardiac function, we designed a cell-permeable peptide, which we termed trans-activator of transcription (TAT)-AKAD for TAT-conjugated A-kinase-anchoring disruptor, using the PKA binding region of AKAP10 and tested the effects of this peptide in isolated cardiac myocytes and in Langendorff-perfused mouse hearts. We initially validated TAT-AKAD as a PKA localization inhibitor in cardiac myocytes by the use of confocal microscopy and cellular fractionation to show that treatment with the peptide disrupts type I and type II PKA regulatory subunits. Knockdown of PKA activity was demonstrated by decrease in phosphorylation of phospholamban and troponin I after beta-adrenergic stimulation in isolated myocytes. Treatment with TAT-AKAD reduced myocyte shortening and rates of contraction and relaxation. Injection of TAT-AKAD (1 microM), but not scrambled control peptide, into the coronary circulation of isolated perfused hearts rapidly (<1 min) and reversibly decreased heart rate and peak left ventricular developed pressure. TAT-AKAD also had a pronounced effect on developed pressure (-dP/dt), consistent with a delayed relaxation of the heart. The effects of TAT-AKAD on heart rate and contractility persisted in hearts pretreated with isoproterenol. Disruption of PKA localization with TAT-AKAD thus had negative effects on chronotropy, inotropy, and lusitropy, thereby indicating a key role for AKAP-targeted PKA in control of heart rate and contractile function.

Phospholamban

Contractility

Cardiac myocyte

10.1074/jbc.m110.146589

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Small Molecule Inhibitor of Antigen Binding and Presentation by HLA-DR2b as a Therapeutic Strategy for the Treatment of Multiple Sclerosis

The Journal of Immunology (2013)

Niannian Ji Animesh Somanaboeina Aakanksha Dixit Kazuyuki Kawamura Neil J. Hayward

Abstract The strong association of HLA-DR2b (DRB1*1501) with multiple sclerosis (MS) suggests this molecule as prime target for specific immunotherapy. Inhibition of HLA-DR2b–restricted myelin-specific T cells has the potential to selectively prevent CNS pathology mediated by these MHC molecules without undesired global immunosuppression. In this study, we report development of a highly selective small molecule inhibitor of peptide binding and presentation by HLA-DR2b. PV-267, the candidate molecule used in these studies, inhibited cytokine production and proliferation of myelin-specific HLA-DR2b–restricted T cells. PV-267 had no significant effect on T cell responses mediated by other MHC class II molecules, including HLA-DR1, -DR4, or -DR9. Importantly, PV-267 did not induce nonspecific immune activation of human PBMC. Lastly, PV-267 showed treatment efficacy both in preventing experimental autoimmune encephalomyelitis and in treating established disease. The results suggest that blocking the MS-associated HLA-DR2b allele with small molecule inhibitors may be a promising therapeutic strategy for the treatment of MS.

Immunosuppression

10.4049/jimmunol.1300407

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Designing isoform-specific peptide disruptors of protein kinase A localization

Proceedings of the National Academy of Sciences (2003)

Lora Hamuro Yuliang Ma Stefan Kammerer Ulrich Reineke Chris Self

A kinase-anchoring proteins (AKAPs) coordinate cAMP-mediated signaling by binding and localizing cAMP-dependent protein kinase (PKA), using an amphipathic helical docking motif. Peptide disruptors of PKA localization that mimic this helix have been used successfully to assess the involvement of PKA in specific signaling pathways. However, these peptides were developed as disruptors for the type II regulatory subunit (RII) even though both RI and RII isoforms can bind to AKAPs and have discrete functions. To evaluate the effects of each localized isoform, we designed peptides that specifically bind to either RI or RII. Using a peptide array, we have defined the minimal binding sequence of dual specific-AKAP 2 ( d -AKAP2), which binds tightly to both RI and RII. Side-chain requirements for affinity and isoform specificity were evaluated by using a peptide substitution array where each position along the A kinase binding domain of d -AKAP2 was substituted by the other 19 l -amino acids. This array comprises 513 single-site substitution analogs of the d -AKAP2 sequence. Peptides containing single and multiple mutations were evaluated in a quantitative fluorescence binding assay and a cell-based colocalization assay. This strategy has allowed us to design peptides with high affinity ( K D = 1–2 nM) and high specificity for RIα versus RIIα. These isoform-specific peptides will be invaluable tools to evaluate functional differences between localized RI and RII PKA and are RIα-specific disruptors. This array-based analysis also provides a foundation for biophysical analysis of this docking motif.

Docking (animal)

10.1073/pnas.2628038100

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Citations (130)