Minimal-Size, Constrained Corticotropin-Releasing Factor Agonists with i−(i+3) Glu−Lys and Lys−Glu Bridges
In three earlier publications (Miranda et al. J. Med. Chem. 1994, 37, 1450−1459; 1997, 40, 3651−3658; Gulyas et al. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 10575−10579) we have hypothesized that covalent constraints such as side-chain-to-side-chain lactam rings would stabilize an α-helical conformat...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 1998-07, Vol.41 (14), p.2614-2620 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 2620 |
|---|---|
| container_issue | 14 |
| container_start_page | 2614 |
| container_title | Journal of medicinal chemistry |
| container_volume | 41 |
| creator | Rivier, Jean Lahrichi, Sabine L Gulyas, Jozsef Erchegyi, Judit Koerber, Steven C Craig, A. Grey Corrigan, Anne Rivier, Catherine Vale, Wylie |
| description | In three earlier publications (Miranda et al. J. Med. Chem. 1994, 37, 1450−1459; 1997, 40, 3651−3658; Gulyas et al. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 10575−10579) we have hypothesized that covalent constraints such as side-chain-to-side-chain lactam rings would stabilize an α-helical conformation shown to be important for the recognition and binding of the CRF C-terminus 30 residues, to CRF receptors. These studies led to the discovery of useful CRF antagonists such as α-helical CRF (α-hel-CRF) and Astressin both in vitro and in vivo. To test the hypothesis that such lactam rings may also be modulating activation of the receptor when introduced at the N-terminus of CRF, we studied the influence of the successive introduction from residues 4 to 14 of a cyclo(i,i+3)[Lys i −Glu( i +3)] and a cyclo(i,i+3)[Glu i −Lys( i +3)] bridge on the in vitro potency of the agonist [Ac-Pro4,dPhe12,Nle21,38]hCRF(4 - 41) and related compounds. We have also introduced the favored cyclo(Glu30−Lys33) substitution found to be remarkable in several families of antagonists (such as Astressin) and in a number of CRF agonists and investigated the role of residues 4−8 on receptor activation using successive deletions. Earlier studies had shown that in both oCRF and α-helical CRF, deletion of residues 1−6, 1−7, and 1−8 led to gradual loss of intrinsic activity (IA) (from 50% IA to |
| doi_str_mv | 10.1021/jm980164e |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_79985180</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>79985180</sourcerecordid><originalsourceid>FETCH-LOGICAL-a292t-5e536042ab7fb5597e86ba15db035beb911dae506c8af2ab68ba558b4bbee0003</originalsourceid><addsrcrecordid>eNptkMFu1DAQhi1EVZbCgQdA8gEQVQnYTuwkx3ahXaQtIFouXKxxMlm8zdqLnQjKE3DuI_Ik9WpXe-I0Y_-fRjMfIc84e8uZ4O-Wq7piXBX4gEy4FCwrKlY8JBPGhMiEEvkj8jjGJWMs5yI_JIe1kpwrOSHrS-vsCvrsyv7BN3TqXRwCWIdt6sNgGz8Ev7Yu-4o9QrRuQc-hGXygpwvvbBwi_WWHH9T--3v32p7kx_SiH1M_v40UXEtTTa_0R8-CbRcYn5CDDvqIT3f1iHw7_3A9nWXzzxcfp6fzDEQthkyizBUrBJiyM1LWJVbKAJetYbk0aGrOW0DJVFNBlyhVGZCyMoUxiJs7j8ir7dx18D9HjINe2dhg34NDP0Zd1nUlebUBj7dgE3yMATu9DslIuNWc6Y1dvbeb2Oe7oaNZYbsndzpT_mKXQ2yg7wK4xsY9JnKRdiwTlm2x5A9_72MIN1qVeSn19ZcrfTk7m03ff_quN_zLLQ9N1Es_BpfM_We9e1WDn9g</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>79985180</pqid></control><display><type>article</type><title>Minimal-Size, Constrained Corticotropin-Releasing Factor Agonists with i−(i+3) Glu−Lys and Lys−Glu Bridges</title><source>MEDLINE</source><source>ACS Publications</source><creator>Rivier, Jean ; Lahrichi, Sabine L ; Gulyas, Jozsef ; Erchegyi, Judit ; Koerber, Steven C ; Craig, A. Grey ; Corrigan, Anne ; Rivier, Catherine ; Vale, Wylie</creator><creatorcontrib>Rivier, Jean ; Lahrichi, Sabine L ; Gulyas, Jozsef ; Erchegyi, Judit ; Koerber, Steven C ; Craig, A. Grey ; Corrigan, Anne ; Rivier, Catherine ; Vale, Wylie</creatorcontrib><description>In three earlier publications (Miranda et al. J. Med. Chem. 1994, 37, 1450−1459; 1997, 40, 3651−3658; Gulyas et al. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 10575−10579) we have hypothesized that covalent constraints such as side-chain-to-side-chain lactam rings would stabilize an α-helical conformation shown to be important for the recognition and binding of the CRF C-terminus 30 residues, to CRF receptors. These studies led to the discovery of useful CRF antagonists such as α-helical CRF (α-hel-CRF) and Astressin both in vitro and in vivo. To test the hypothesis that such lactam rings may also be modulating activation of the receptor when introduced at the N-terminus of CRF, we studied the influence of the successive introduction from residues 4 to 14 of a cyclo(i,i+3)[Lys i −Glu( i +3)] and a cyclo(i,i+3)[Glu i −Lys( i +3)] bridge on the in vitro potency of the agonist [Ac-Pro4,dPhe12,Nle21,38]hCRF(4 - 41) and related compounds. We have also introduced the favored cyclo(Glu30−Lys33) substitution found to be remarkable in several families of antagonists (such as Astressin) and in a number of CRF agonists and investigated the role of residues 4−8 on receptor activation using successive deletions. Earlier studies had shown that in both oCRF and α-helical CRF, deletion of residues 1−6, 1−7, and 1−8 led to gradual loss of intrinsic activity (IA) (from 50% IA to <10% IA) resulting in α-hel-CRF being a potent competitive antagonist. We show that acetylation of the N-terminus of these fragments generally increases potency by a factor of 2−3 with no influence on IA. While cyclo(30−33)[Ac-Leu8,dPhe12,Nle21,Glu30,Lys33,Nle38]hCRF(8 - 41) (30) is the shortest reported analogue of CRF to be equipotent to CRF (70% IA), the corresponding linear analogue (31) is 120 times less potent (59% IA). Addition of one amino acid at the N-terminus {cyclo(30−33)[Ac-Ser7,dPhe12,Nle21,Glu30,Lys33,Nle38]hCRF(7 - 41) (28)} results in a 5-fold increase in agonist potency and full intrinsic activity (113%). The most favored modifications were also introduced in other members of the CRF family including sauvagine (Sau), urotensin (Utn), urocortin (Ucn), and α-hel-CRF. Parallel and consistent results were obtained suggesting that the lactam cyclization at residues 29−32 and 30−33 (for the members of the CRF family with 40 and 41 amino acid residues, respectively) will induce (in the shortened agonists) a structural constraint (α-helix) that stabilizes a bioactive conformation similar to that shown in the Astressin family of CRF antagonists and that residue 8 (leucine or isoleucine) bears the sole responsibility for activation of the receptor since deletion of that residue leads to potent antagonists (Gulyas et al. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 10575−10579).</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm980164e</identifier><identifier>PMID: 9651165</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Amino Acid Sequence ; Animals ; Biological and medical sciences ; Cells, Cultured ; Chromatography, High Pressure Liquid ; Corticotropin-Releasing Hormone - agonists ; Corticotropin-Releasing Hormone - analogs & derivatives ; Corticotropin-Releasing Hormone - chemical synthesis ; Corticotropin-Releasing Hormone - pharmacology ; Electrophoresis, Capillary ; Glutamine - chemistry ; Hormones. Endocrine system ; Humans ; Lysine - chemistry ; Mass Spectrometry ; Medical sciences ; Molecular Sequence Data ; Peptides, Cyclic - chemical synthesis ; Peptides, Cyclic - chemistry ; Peptides, Cyclic - pharmacology ; Pharmacology. Drug treatments ; Pituitary Gland, Anterior - cytology ; Pituitary Gland, Anterior - drug effects ; Pituitary Gland, Anterior - metabolism ; Rats ; Rats, Sprague-Dawley ; Sheep ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1998-07, Vol.41 (14), p.2614-2620</ispartof><rights>Copyright © 1998 American Chemical Society</rights><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a292t-5e536042ab7fb5597e86ba15db035beb911dae506c8af2ab68ba558b4bbee0003</citedby><cites>FETCH-LOGICAL-a292t-5e536042ab7fb5597e86ba15db035beb911dae506c8af2ab68ba558b4bbee0003</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm980164e$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm980164e$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2763,27075,27923,27924,56737,56787</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2325587$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9651165$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rivier, Jean</creatorcontrib><creatorcontrib>Lahrichi, Sabine L</creatorcontrib><creatorcontrib>Gulyas, Jozsef</creatorcontrib><creatorcontrib>Erchegyi, Judit</creatorcontrib><creatorcontrib>Koerber, Steven C</creatorcontrib><creatorcontrib>Craig, A. Grey</creatorcontrib><creatorcontrib>Corrigan, Anne</creatorcontrib><creatorcontrib>Rivier, Catherine</creatorcontrib><creatorcontrib>Vale, Wylie</creatorcontrib><title>Minimal-Size, Constrained Corticotropin-Releasing Factor Agonists with i−(i+3) Glu−Lys and Lys−Glu Bridges</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>In three earlier publications (Miranda et al. J. Med. Chem. 1994, 37, 1450−1459; 1997, 40, 3651−3658; Gulyas et al. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 10575−10579) we have hypothesized that covalent constraints such as side-chain-to-side-chain lactam rings would stabilize an α-helical conformation shown to be important for the recognition and binding of the CRF C-terminus 30 residues, to CRF receptors. These studies led to the discovery of useful CRF antagonists such as α-helical CRF (α-hel-CRF) and Astressin both in vitro and in vivo. To test the hypothesis that such lactam rings may also be modulating activation of the receptor when introduced at the N-terminus of CRF, we studied the influence of the successive introduction from residues 4 to 14 of a cyclo(i,i+3)[Lys i −Glu( i +3)] and a cyclo(i,i+3)[Glu i −Lys( i +3)] bridge on the in vitro potency of the agonist [Ac-Pro4,dPhe12,Nle21,38]hCRF(4 - 41) and related compounds. We have also introduced the favored cyclo(Glu30−Lys33) substitution found to be remarkable in several families of antagonists (such as Astressin) and in a number of CRF agonists and investigated the role of residues 4−8 on receptor activation using successive deletions. Earlier studies had shown that in both oCRF and α-helical CRF, deletion of residues 1−6, 1−7, and 1−8 led to gradual loss of intrinsic activity (IA) (from 50% IA to <10% IA) resulting in α-hel-CRF being a potent competitive antagonist. We show that acetylation of the N-terminus of these fragments generally increases potency by a factor of 2−3 with no influence on IA. While cyclo(30−33)[Ac-Leu8,dPhe12,Nle21,Glu30,Lys33,Nle38]hCRF(8 - 41) (30) is the shortest reported analogue of CRF to be equipotent to CRF (70% IA), the corresponding linear analogue (31) is 120 times less potent (59% IA). Addition of one amino acid at the N-terminus {cyclo(30−33)[Ac-Ser7,dPhe12,Nle21,Glu30,Lys33,Nle38]hCRF(7 - 41) (28)} results in a 5-fold increase in agonist potency and full intrinsic activity (113%). The most favored modifications were also introduced in other members of the CRF family including sauvagine (Sau), urotensin (Utn), urocortin (Ucn), and α-hel-CRF. Parallel and consistent results were obtained suggesting that the lactam cyclization at residues 29−32 and 30−33 (for the members of the CRF family with 40 and 41 amino acid residues, respectively) will induce (in the shortened agonists) a structural constraint (α-helix) that stabilizes a bioactive conformation similar to that shown in the Astressin family of CRF antagonists and that residue 8 (leucine or isoleucine) bears the sole responsibility for activation of the receptor since deletion of that residue leads to potent antagonists (Gulyas et al. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 10575−10579).</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cells, Cultured</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Corticotropin-Releasing Hormone - agonists</subject><subject>Corticotropin-Releasing Hormone - analogs & derivatives</subject><subject>Corticotropin-Releasing Hormone - chemical synthesis</subject><subject>Corticotropin-Releasing Hormone - pharmacology</subject><subject>Electrophoresis, Capillary</subject><subject>Glutamine - chemistry</subject><subject>Hormones. Endocrine system</subject><subject>Humans</subject><subject>Lysine - chemistry</subject><subject>Mass Spectrometry</subject><subject>Medical sciences</subject><subject>Molecular Sequence Data</subject><subject>Peptides, Cyclic - chemical synthesis</subject><subject>Peptides, Cyclic - chemistry</subject><subject>Peptides, Cyclic - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Pituitary Gland, Anterior - cytology</subject><subject>Pituitary Gland, Anterior - drug effects</subject><subject>Pituitary Gland, Anterior - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Sheep</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkMFu1DAQhi1EVZbCgQdA8gEQVQnYTuwkx3ahXaQtIFouXKxxMlm8zdqLnQjKE3DuI_Ik9WpXe-I0Y_-fRjMfIc84e8uZ4O-Wq7piXBX4gEy4FCwrKlY8JBPGhMiEEvkj8jjGJWMs5yI_JIe1kpwrOSHrS-vsCvrsyv7BN3TqXRwCWIdt6sNgGz8Ev7Yu-4o9QrRuQc-hGXygpwvvbBwi_WWHH9T--3v32p7kx_SiH1M_v40UXEtTTa_0R8-CbRcYn5CDDvqIT3f1iHw7_3A9nWXzzxcfp6fzDEQthkyizBUrBJiyM1LWJVbKAJetYbk0aGrOW0DJVFNBlyhVGZCyMoUxiJs7j8ir7dx18D9HjINe2dhg34NDP0Zd1nUlebUBj7dgE3yMATu9DslIuNWc6Y1dvbeb2Oe7oaNZYbsndzpT_mKXQ2yg7wK4xsY9JnKRdiwTlm2x5A9_72MIN1qVeSn19ZcrfTk7m03ff_quN_zLLQ9N1Es_BpfM_We9e1WDn9g</recordid><startdate>19980702</startdate><enddate>19980702</enddate><creator>Rivier, Jean</creator><creator>Lahrichi, Sabine L</creator><creator>Gulyas, Jozsef</creator><creator>Erchegyi, Judit</creator><creator>Koerber, Steven C</creator><creator>Craig, A. Grey</creator><creator>Corrigan, Anne</creator><creator>Rivier, Catherine</creator><creator>Vale, Wylie</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>19980702</creationdate><title>Minimal-Size, Constrained Corticotropin-Releasing Factor Agonists with i−(i+3) Glu−Lys and Lys−Glu Bridges</title><author>Rivier, Jean ; Lahrichi, Sabine L ; Gulyas, Jozsef ; Erchegyi, Judit ; Koerber, Steven C ; Craig, A. Grey ; Corrigan, Anne ; Rivier, Catherine ; Vale, Wylie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a292t-5e536042ab7fb5597e86ba15db035beb911dae506c8af2ab68ba558b4bbee0003</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cells, Cultured</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Corticotropin-Releasing Hormone - agonists</topic><topic>Corticotropin-Releasing Hormone - analogs & derivatives</topic><topic>Corticotropin-Releasing Hormone - chemical synthesis</topic><topic>Corticotropin-Releasing Hormone - pharmacology</topic><topic>Electrophoresis, Capillary</topic><topic>Glutamine - chemistry</topic><topic>Hormones. Endocrine system</topic><topic>Humans</topic><topic>Lysine - chemistry</topic><topic>Mass Spectrometry</topic><topic>Medical sciences</topic><topic>Molecular Sequence Data</topic><topic>Peptides, Cyclic - chemical synthesis</topic><topic>Peptides, Cyclic - chemistry</topic><topic>Peptides, Cyclic - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Pituitary Gland, Anterior - cytology</topic><topic>Pituitary Gland, Anterior - drug effects</topic><topic>Pituitary Gland, Anterior - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Sheep</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rivier, Jean</creatorcontrib><creatorcontrib>Lahrichi, Sabine L</creatorcontrib><creatorcontrib>Gulyas, Jozsef</creatorcontrib><creatorcontrib>Erchegyi, Judit</creatorcontrib><creatorcontrib>Koerber, Steven C</creatorcontrib><creatorcontrib>Craig, A. Grey</creatorcontrib><creatorcontrib>Corrigan, Anne</creatorcontrib><creatorcontrib>Rivier, Catherine</creatorcontrib><creatorcontrib>Vale, Wylie</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rivier, Jean</au><au>Lahrichi, Sabine L</au><au>Gulyas, Jozsef</au><au>Erchegyi, Judit</au><au>Koerber, Steven C</au><au>Craig, A. Grey</au><au>Corrigan, Anne</au><au>Rivier, Catherine</au><au>Vale, Wylie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Minimal-Size, Constrained Corticotropin-Releasing Factor Agonists with i−(i+3) Glu−Lys and Lys−Glu Bridges</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1998-07-02</date><risdate>1998</risdate><volume>41</volume><issue>14</issue><spage>2614</spage><epage>2620</epage><pages>2614-2620</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>In three earlier publications (Miranda et al. J. Med. Chem. 1994, 37, 1450−1459; 1997, 40, 3651−3658; Gulyas et al. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 10575−10579) we have hypothesized that covalent constraints such as side-chain-to-side-chain lactam rings would stabilize an α-helical conformation shown to be important for the recognition and binding of the CRF C-terminus 30 residues, to CRF receptors. These studies led to the discovery of useful CRF antagonists such as α-helical CRF (α-hel-CRF) and Astressin both in vitro and in vivo. To test the hypothesis that such lactam rings may also be modulating activation of the receptor when introduced at the N-terminus of CRF, we studied the influence of the successive introduction from residues 4 to 14 of a cyclo(i,i+3)[Lys i −Glu( i +3)] and a cyclo(i,i+3)[Glu i −Lys( i +3)] bridge on the in vitro potency of the agonist [Ac-Pro4,dPhe12,Nle21,38]hCRF(4 - 41) and related compounds. We have also introduced the favored cyclo(Glu30−Lys33) substitution found to be remarkable in several families of antagonists (such as Astressin) and in a number of CRF agonists and investigated the role of residues 4−8 on receptor activation using successive deletions. Earlier studies had shown that in both oCRF and α-helical CRF, deletion of residues 1−6, 1−7, and 1−8 led to gradual loss of intrinsic activity (IA) (from 50% IA to <10% IA) resulting in α-hel-CRF being a potent competitive antagonist. We show that acetylation of the N-terminus of these fragments generally increases potency by a factor of 2−3 with no influence on IA. While cyclo(30−33)[Ac-Leu8,dPhe12,Nle21,Glu30,Lys33,Nle38]hCRF(8 - 41) (30) is the shortest reported analogue of CRF to be equipotent to CRF (70% IA), the corresponding linear analogue (31) is 120 times less potent (59% IA). Addition of one amino acid at the N-terminus {cyclo(30−33)[Ac-Ser7,dPhe12,Nle21,Glu30,Lys33,Nle38]hCRF(7 - 41) (28)} results in a 5-fold increase in agonist potency and full intrinsic activity (113%). The most favored modifications were also introduced in other members of the CRF family including sauvagine (Sau), urotensin (Utn), urocortin (Ucn), and α-hel-CRF. Parallel and consistent results were obtained suggesting that the lactam cyclization at residues 29−32 and 30−33 (for the members of the CRF family with 40 and 41 amino acid residues, respectively) will induce (in the shortened agonists) a structural constraint (α-helix) that stabilizes a bioactive conformation similar to that shown in the Astressin family of CRF antagonists and that residue 8 (leucine or isoleucine) bears the sole responsibility for activation of the receptor since deletion of that residue leads to potent antagonists (Gulyas et al. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 10575−10579).</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>9651165</pmid><doi>10.1021/jm980164e</doi><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1998-07, Vol.41 (14), p.2614-2620 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_79985180 |
| source | MEDLINE; ACS Publications |
| subjects | Amino Acid Sequence Animals Biological and medical sciences Cells, Cultured Chromatography, High Pressure Liquid Corticotropin-Releasing Hormone - agonists Corticotropin-Releasing Hormone - analogs & derivatives Corticotropin-Releasing Hormone - chemical synthesis Corticotropin-Releasing Hormone - pharmacology Electrophoresis, Capillary Glutamine - chemistry Hormones. Endocrine system Humans Lysine - chemistry Mass Spectrometry Medical sciences Molecular Sequence Data Peptides, Cyclic - chemical synthesis Peptides, Cyclic - chemistry Peptides, Cyclic - pharmacology Pharmacology. Drug treatments Pituitary Gland, Anterior - cytology Pituitary Gland, Anterior - drug effects Pituitary Gland, Anterior - metabolism Rats Rats, Sprague-Dawley Sheep Structure-Activity Relationship |
| title | Minimal-Size, Constrained Corticotropin-Releasing Factor Agonists with i−(i+3) Glu−Lys and Lys−Glu Bridges |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-11T21%3A21%3A00IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Minimal-Size,%20Constrained%20Corticotropin-Releasing%20Factor%20Agonists%20with%20i%E2%88%92(i+3)%20Glu%E2%88%92Lys%20and%20Lys%E2%88%92Glu%20Bridges&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Rivier,%20Jean&rft.date=1998-07-02&rft.volume=41&rft.issue=14&rft.spage=2614&rft.epage=2620&rft.pages=2614-2620&rft.issn=0022-2623&rft.eissn=1520-4804&rft.coden=JMCMAR&rft_id=info:doi/10.1021/jm980164e&rft_dat=%3Cproquest_cross%3E79985180%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=79985180&rft_id=info:pmid/9651165&rfr_iscdi=true |