Conformationally defined adrenergic agents. 4. 1-(Aminomethyl)phthalans: synthesis and pharmacological consequences of the phthalan ring oxygen atom
The synthesis of a series of 1-(aminomethyl)phthalans 1b is reported. The radioligand binding to alpha 1- and alpha 2-receptors and the in vitro pharmacology in alpha 1 (rabbit aorta) and alpha 2 (phenoxybenzamine-pretreated dog saphenous vein) tissues were determined and were compared to the activi...
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| Veröffentlicht in: | Journal of medicinal chemistry 1987-01, Vol.30 (1), p.178-184 |
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| container_issue | 1 |
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| container_title | Journal of medicinal chemistry |
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| creator | DeBernardis, John F Arendsen, David L Kyncl, John J Kerkman, Daniel J |
| description | The synthesis of a series of 1-(aminomethyl)phthalans 1b is reported. The radioligand binding to alpha 1- and alpha 2-receptors and the in vitro pharmacology in alpha 1 (rabbit aorta) and alpha 2 (phenoxybenzamine-pretreated dog saphenous vein) tissues were determined and were compared to the activity of the corresponding 1-(aminomethyl)indans. The activity of this series of phthalans was found to be consistent with the electrostatic repulsion hypothesis that was used to design the parent indan (ERBCOP) compounds. The effect of the phthalan ring oxygenation was to somewhat improve alpha 1-receptor potency relative to the 6-ERBCOP indans without having a general effect on the alpha 2-receptor potency. We conclude from the overall pattern of activity that while the norepinephrine type beta-hydroxyl group may be beneficial for binding to the alpha 1-adrenoceptor, it is not required for strong binding to or full stimulation of the alpha 2-adrenergic receptor, provided that the conformational mobility associated with the phenylethylamine is restricted and maintained in a favorable conformation for receptor interaction. |
| doi_str_mv | 10.1021/jm00384a030 |
| format | Article |
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The radioligand binding to alpha 1- and alpha 2-receptors and the in vitro pharmacology in alpha 1 (rabbit aorta) and alpha 2 (phenoxybenzamine-pretreated dog saphenous vein) tissues were determined and were compared to the activity of the corresponding 1-(aminomethyl)indans. The activity of this series of phthalans was found to be consistent with the electrostatic repulsion hypothesis that was used to design the parent indan (ERBCOP) compounds. The effect of the phthalan ring oxygenation was to somewhat improve alpha 1-receptor potency relative to the 6-ERBCOP indans without having a general effect on the alpha 2-receptor potency. We conclude from the overall pattern of activity that while the norepinephrine type beta-hydroxyl group may be beneficial for binding to the alpha 1-adrenoceptor, it is not required for strong binding to or full stimulation of the alpha 2-adrenergic receptor, provided that the conformational mobility associated with the phenylethylamine is restricted and maintained in a favorable conformation for receptor interaction.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00384a030</identifier><identifier>PMID: 2879916</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Adrenergic alpha-Agonists - chemical synthesis ; Animals ; Benzofurans - chemical synthesis ; Benzofurans - pharmacology ; Brain - metabolism ; Dogs ; Female ; In Vitro Techniques ; Indicators and Reagents ; Kinetics ; Liver - metabolism ; Magnetic Resonance Spectroscopy ; Male ; Mass Spectrometry ; Methylamines - chemical synthesis ; Methylamines - pharmacology ; Muscle Contraction - drug effects ; Muscle, Smooth, Vascular - drug effects ; Muscle, Smooth, Vascular - physiology ; Rabbits ; Rats ; Rats, Inbred Strains ; Receptors, Adrenergic, alpha - drug effects ; Receptors, Adrenergic, alpha - metabolism ; Spectrophotometry, Infrared ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1987-01, Vol.30 (1), p.178-184</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a286t-caea944bb9e5884339eb2e14fbf0da9a7d85831827e6f5d9c4e2b27a623918953</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00384a030$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00384a030$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2751,27055,27903,27904,56716,56766</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/2879916$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>DeBernardis, John F</creatorcontrib><creatorcontrib>Arendsen, David L</creatorcontrib><creatorcontrib>Kyncl, John J</creatorcontrib><creatorcontrib>Kerkman, Daniel J</creatorcontrib><title>Conformationally defined adrenergic agents. 4. 1-(Aminomethyl)phthalans: synthesis and pharmacological consequences of the phthalan ring oxygen atom</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The synthesis of a series of 1-(aminomethyl)phthalans 1b is reported. The radioligand binding to alpha 1- and alpha 2-receptors and the in vitro pharmacology in alpha 1 (rabbit aorta) and alpha 2 (phenoxybenzamine-pretreated dog saphenous vein) tissues were determined and were compared to the activity of the corresponding 1-(aminomethyl)indans. The activity of this series of phthalans was found to be consistent with the electrostatic repulsion hypothesis that was used to design the parent indan (ERBCOP) compounds. The effect of the phthalan ring oxygenation was to somewhat improve alpha 1-receptor potency relative to the 6-ERBCOP indans without having a general effect on the alpha 2-receptor potency. We conclude from the overall pattern of activity that while the norepinephrine type beta-hydroxyl group may be beneficial for binding to the alpha 1-adrenoceptor, it is not required for strong binding to or full stimulation of the alpha 2-adrenergic receptor, provided that the conformational mobility associated with the phenylethylamine is restricted and maintained in a favorable conformation for receptor interaction.</description><subject>Adrenergic alpha-Agonists - chemical synthesis</subject><subject>Animals</subject><subject>Benzofurans - chemical synthesis</subject><subject>Benzofurans - pharmacology</subject><subject>Brain - metabolism</subject><subject>Dogs</subject><subject>Female</subject><subject>In Vitro Techniques</subject><subject>Indicators and Reagents</subject><subject>Kinetics</subject><subject>Liver - metabolism</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Male</subject><subject>Mass Spectrometry</subject><subject>Methylamines - chemical synthesis</subject><subject>Methylamines - pharmacology</subject><subject>Muscle Contraction - drug effects</subject><subject>Muscle, Smooth, Vascular - drug effects</subject><subject>Muscle, Smooth, Vascular - physiology</subject><subject>Rabbits</subject><subject>Rats</subject><subject>Rats, Inbred Strains</subject><subject>Receptors, Adrenergic, alpha - drug effects</subject><subject>Receptors, Adrenergic, alpha - metabolism</subject><subject>Spectrophotometry, Infrared</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1987</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkc1v1DAQxS0EKkvhxBnJJz6Esvgrid1btUALqkQRi8TNmiSTTZbEXuys1Pwf_MG42m3VA6c5vN-8Gb1HyEvOlpwJ_mE7Mia1AibZI7LguWCZ0kw9JgvGhMhEIeRT8izGLUscF_KEnAhdGsOLBfm78q71YYSp9w6GYaYNtr3DhkIT0GHY9DWFDbopLqlaUp69PR9750ecunl4t-umDgZw8YzG2U0dxj5ScA3ddZBMaz_4ZAADrb2L-GePrsZIfUsTSu-WaejdhvqbOZ2hMPnxOXnSwhDxxXGekp-fP61Xl9nVt4svq_OrDIQupqwGBKNUVRnMtVZSGqwEctVWLWvAQNnoXEuuRYlFmzemVigqUULKw3BtcnlKXh98d8Gn3-Jkxz7WOKSf0O-jLUupc2VYAt8fwDr4GAO2dhf6EcJsObO3HdgHHST61dF2X43Y3LPH0JOeHfQ-TnhzL0P4bYtSlrldX_-wv-TXdfn9-qO9TPybAw91tFu_D6mo-N_L_wDTsqAm</recordid><startdate>19870101</startdate><enddate>19870101</enddate><creator>DeBernardis, John F</creator><creator>Arendsen, David L</creator><creator>Kyncl, John J</creator><creator>Kerkman, Daniel J</creator><general>American Chemical Society</general><scope>BSCLL</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>19870101</creationdate><title>Conformationally defined adrenergic agents. 4. 1-(Aminomethyl)phthalans: synthesis and pharmacological consequences of the phthalan ring oxygen atom</title><author>DeBernardis, John F ; Arendsen, David L ; Kyncl, John J ; Kerkman, Daniel J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a286t-caea944bb9e5884339eb2e14fbf0da9a7d85831827e6f5d9c4e2b27a623918953</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1987</creationdate><topic>Adrenergic alpha-Agonists - chemical synthesis</topic><topic>Animals</topic><topic>Benzofurans - chemical synthesis</topic><topic>Benzofurans - pharmacology</topic><topic>Brain - metabolism</topic><topic>Dogs</topic><topic>Female</topic><topic>In Vitro Techniques</topic><topic>Indicators and Reagents</topic><topic>Kinetics</topic><topic>Liver - metabolism</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Male</topic><topic>Mass Spectrometry</topic><topic>Methylamines - chemical synthesis</topic><topic>Methylamines - pharmacology</topic><topic>Muscle Contraction - drug effects</topic><topic>Muscle, Smooth, Vascular - drug effects</topic><topic>Muscle, Smooth, Vascular - physiology</topic><topic>Rabbits</topic><topic>Rats</topic><topic>Rats, Inbred Strains</topic><topic>Receptors, Adrenergic, alpha - drug effects</topic><topic>Receptors, Adrenergic, alpha - metabolism</topic><topic>Spectrophotometry, Infrared</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>DeBernardis, John F</creatorcontrib><creatorcontrib>Arendsen, David L</creatorcontrib><creatorcontrib>Kyncl, John J</creatorcontrib><creatorcontrib>Kerkman, Daniel J</creatorcontrib><collection>Istex</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>DeBernardis, John F</au><au>Arendsen, David L</au><au>Kyncl, John J</au><au>Kerkman, Daniel J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Conformationally defined adrenergic agents. 4. 1-(Aminomethyl)phthalans: synthesis and pharmacological consequences of the phthalan ring oxygen atom</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1987-01-01</date><risdate>1987</risdate><volume>30</volume><issue>1</issue><spage>178</spage><epage>184</epage><pages>178-184</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The synthesis of a series of 1-(aminomethyl)phthalans 1b is reported. The radioligand binding to alpha 1- and alpha 2-receptors and the in vitro pharmacology in alpha 1 (rabbit aorta) and alpha 2 (phenoxybenzamine-pretreated dog saphenous vein) tissues were determined and were compared to the activity of the corresponding 1-(aminomethyl)indans. The activity of this series of phthalans was found to be consistent with the electrostatic repulsion hypothesis that was used to design the parent indan (ERBCOP) compounds. The effect of the phthalan ring oxygenation was to somewhat improve alpha 1-receptor potency relative to the 6-ERBCOP indans without having a general effect on the alpha 2-receptor potency. We conclude from the overall pattern of activity that while the norepinephrine type beta-hydroxyl group may be beneficial for binding to the alpha 1-adrenoceptor, it is not required for strong binding to or full stimulation of the alpha 2-adrenergic receptor, provided that the conformational mobility associated with the phenylethylamine is restricted and maintained in a favorable conformation for receptor interaction.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>2879916</pmid><doi>10.1021/jm00384a030</doi><tpages>7</tpages></addata></record> |
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| subjects | Adrenergic alpha-Agonists - chemical synthesis Animals Benzofurans - chemical synthesis Benzofurans - pharmacology Brain - metabolism Dogs Female In Vitro Techniques Indicators and Reagents Kinetics Liver - metabolism Magnetic Resonance Spectroscopy Male Mass Spectrometry Methylamines - chemical synthesis Methylamines - pharmacology Muscle Contraction - drug effects Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - physiology Rabbits Rats Rats, Inbred Strains Receptors, Adrenergic, alpha - drug effects Receptors, Adrenergic, alpha - metabolism Spectrophotometry, Infrared Structure-Activity Relationship |
| title | Conformationally defined adrenergic agents. 4. 1-(Aminomethyl)phthalans: synthesis and pharmacological consequences of the phthalan ring oxygen atom |
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