Several thyroid hormone analogs have been tested for thyromimetic activity on rat brain and liver subcellular organelles. The compounds were administered immediately after thyroidectomy to 90 g male S-D rats for 10 days, by daily s.c. injection. In cerebral cortex and liver we measured the activities of mitochondrial succinate cytochrome c reductase and a-GPD, and nuclear RNA polymerase I. Brain mitochondrial enzymes were unchanged in thyroidectomized (Tx) and in Tx-treated rats, whereas the activities of these enzymes in liver mitochondria were partially restored by the treatments. RNA polymerase I activity in brain and liver dropped significantly 10 days after thyroidectomy and daily injection of thyroid hormones or analogs maintained the nuclear activity at a normal level. Correlation between the structure of thyroid hormone analogs and their subcellular effects is in good agreement with previous binding and in vivo studies. Enzyme activities stimulated by T3 were lowered by replacing the T3 side-chain by an acetic acid group or by substituting the bridged oxygen atom by atom by CO. In contrast, the activity was enhanced by substituting iodine with a 3' isopropyl group. Although less active than iodine, the 3,5-dimethyl substituents may be introduced without a complete loss of nuclear activity.

Chemischer InformationsdienstVolume 13, Issue 49 Other Subjects ChemInform Abstract: COMPUTER GRAPHICS IN DRUG DESIGN: MOLECULAR MODELING OF THYROID HORMONE-PREALBUMIN INTERACTIONS J. M. BLANEY, J. M. BLANEYSearch for more papers by this authorE. C. JORGENSEN, E. C. JORGENSENSearch for more papers by this authorM. L. CONNOLLY, M. L. CONNOLLYSearch for more papers by this authorT. E. FERRIN, T. E. FERRINSearch for more papers by this authorR. LANGRIDGE, R. LANGRIDGESearch for more papers by this authorS. J. OATLEY, S. J. OATLEYSearch for more papers by this authorJ. M. BURRIDGE, J. M. BURRIDGESearch for more papers by this authorC. C. F. BLAKE, C. C. F. BLAKESearch for more papers by this author J. M. BLANEY, J. M. BLANEYSearch for more papers by this authorE. C. JORGENSEN, E. C. JORGENSENSearch for more papers by this authorM. L. CONNOLLY, M. L. CONNOLLYSearch for more papers by this authorT. E. FERRIN, T. E. FERRINSearch for more papers by this authorR. LANGRIDGE, R. LANGRIDGESearch for more papers by this authorS. J. OATLEY, S. J. OATLEYSearch for more papers by this authorJ. M. BURRIDGE, J. M. BURRIDGESearch for more papers by this authorC. C. F. BLAKE, C. C. F. BLAKESearch for more papers by this author First published: December 7, 1982 https://doi.org/10.1002/chin.198249335AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume13, Issue49December 7, 1982 RelatedInformation

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTThyroid hormone binding to human serum prealbumin and rat liver nuclear receptor: kinetics, contribution of the hormone phenolic hydroxyl group, and accommodation of hormone side-chain bulkRalph Somack, Tariq A. Andrea, and Eugene C. JorgensenCite this: Biochemistry 1982, 21, 1, 163–170Publication Date (Print):January 5, 1982Publication History Published online1 May 2002Published inissue 5 January 1982https://pubs.acs.org/doi/10.1021/bi00530a028https://doi.org/10.1021/bi00530a028research-articleACS PublicationsRequest reuse permissionsArticle Views110Altmetric-Citations38LEARN 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

Computer graphics modeling of the thyroxine-prealbumin complex provides a detailed picture of the interactions between thyroxine and prealbumin. A wide variety of thyroid hormone analogue-prealbumin complexes were modeled by calculating the molecular surfaces of the analogues and the prealbumin hormone-binding site. Analogues with high binding affinity were observed to fill more of the hormone-binding site than low-affinity analogues. These surface models described many aspects of the hormone-protein interaction which were not obvious using simple wire models and led us to develop a model which accounts for thyroid hormone-prealbumin structure-activity relationships and ultimately to predict and measure the relative binding affinities of four previously untested thyroid hormone analogues to prealbumin.

Our experiments show that the T3 nonhalogenated analog 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) exhibits the general activities of thyroid hormones. DIMIT delivered to hypothyroid Rat by constant infusion or sc injections increases bodyweight gain, BMR before or after epinephrine and phosphorylative oxidation of liver mitochondria.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTBinding of thyroid hormones and analogs to the human plasma protein prealbuminTariq A. Andrea, Ralph R. Cavalieri, Ira D. Goldfine, and Eugene C. JorgensenCite this: Biochemistry 1980, 19, 1, 55–63Publication Date (Print):January 8, 1980Publication History Published online1 May 2002Published inissue 8 January 1980https://pubs.acs.org/doi/10.1021/bi00542a009https://doi.org/10.1021/bi00542a009research-articleACS PublicationsRequest reuse permissionsArticle Views118Altmetric-Citations56LEARN 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

Theoretical electronic structure calculations on the thyroid hormones and analogues, as well as model hormone--receptor interactions, have been carried out. These studies (a) support the concept that the 4'-OH group is a H-bond donor to the in vivo nuclear receptor and suggest that at the receptor this OH group is trans to the 3' (distal) substituent; (b) indicate that there is an important intramolecular interaction between 3' and 4' substituents, and those 3' substituents that most favor both 4' OH orientation trans to the 3' group and a more acidic OH group substantially increase binding and biological activity; and (c) support the concept that there is a direct correlation between the conformational free energy of the aromatic rings and biological activity.

We present empirical energy calculations on the binding of thyroxine analogs to the plasma protein prealbumin. The results of the calculations suggest a stronger binding affinity for the L isomer than the D, consistent with observed binding affinities. These calculations allow us to rationalize the significantly stronger binding of des-NH3+ than des-COO− analogs of the hormone to the protein.

Chemischer InformationsdienstVolume 8, Issue 12 Physical Organic Chemistry ChemInform Abstract: A THEORETICAL STUDY OF INTRAMOLECULAR HYDROGEN BONDING IN ORTHO-SUBSTITUTED PHENOLS AND THIOPHENOLS S. W. DIETRICH, S. W. DIETRICHSearch for more papers by this authorE. C. JORGENSEN, E. C. JORGENSENSearch for more papers by this authorP. A. KOLLMAN, P. A. KOLLMANSearch for more papers by this authorS. ROTHENBERG, S. ROTHENBERGSearch for more papers by this author S. W. DIETRICH, S. W. DIETRICHSearch for more papers by this authorE. C. JORGENSEN, E. C. JORGENSENSearch for more papers by this authorP. A. KOLLMAN, P. A. KOLLMANSearch for more papers by this authorS. ROTHENBERG, S. ROTHENBERGSearch for more papers by this author First published: March 22, 1977 https://doi.org/10.1002/chin.197712062Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References S. W. DIETRICH, E. C. JORGENSEN, P. A. KOLLMAN, S. ROTHENBERG, A THEORETICAL STUDY OF INTRAMOLECULAR HYDROGEN BONDING IN ORTHO-SUBSTITUTED PHENOLS AND THIOPHENOLS, J. Am. Chem. Soc., 1976, 98, 8310. DOI: 10.1021/ja00442a002; 10.1021/ja00442a002 CASWeb of Science®Google Scholar Volume8, Issue12March 22, 1977 ReferencesRelatedInformation

The present study was undertaken to study the binding of several thyroid hormones and structurally related compounds to human serum thyroxine-binding alpha-globulin (TBG). The source of TBG was normal human serum diluted 1:100 in 0.035 M barbital buffer, pH 7.4. In the binding assays, 125I-thyroxine, unlabeled thyroxine, and diluted serum were incubated for 20 h at 37 degrees in Plexiglas equilibrium dialysis units. Two orders of binding sites were discerned: a high affinity, low capacity binding site with an affinity constant of approximately 2.5 X 10(9) M-1, and a low affinity, very high capacity binding site with an affinity constant of less than 10(6) M-1. Studies with purified TBG, serum deficient in TBG, and purified human serum albumin indicated that the high affinity site represented binding to TBG and the low affinity site represented binging to albumin. The ability of several groups of thyroid hormone analogues to bind to TBG was then investigated. As a result of these studies, the following structural features of thyroid hormones were found to be important for optimal binding activity: (a) the L-alanine side chain conformation, (b) the presence of a 4'-hydroxyl group, (c) the presence of two substituents in the inner and outer rings (positions 3, 5, 3', and 5'), and (d) the presence of either bromines or iodines in the inner ring and iodines in the outer ring. Of lesser importance was the presence of an oxygen atom in the ether position.

Prior studies have demonstrated that the thyroid hormones L-triiodothyronine and L-thyroxine stimulate the rapid uptake of 1-amino-cyclopentane-1-carboxylic acid into isolated rat thymocytes. In the present study the effects of several groups of thyroid hormones and structurally related compounds were investigated to determine the structure-function relations required for stimulation of this membrane process. Particular attention was given to (a) analogues with modifications at the oxygen bridge, the phenolic hydroxyl group, and the group at the 3' position of the outer ring, and (b) the steric orientation of the thyroid hormones. The following were found to be important for maximal activity: (a) the L-isomer configuration, (b) the presence of a 4'-hydroxyl group, (c) the presence of one substituent in both the inner and outer rings (3 and 3' positions), (d) the distal orientation of the 3' substituent in the outer ring of L-triiodothyronine, and (e) the lipophilic character of the 3' substituent. Of lesser importance was the presence of halogen atoms, or an oxygen atom in the ether position. Since these structure-function relations seen in thymocytes parallel in many respects those relations seen in whole-animal studies, it is believed that thymocytes will be a useful tool for further studies of thyroid hormones and their analogues.