Analogs of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 2. The amide bond "B-region"
A series of compounds incorporating replacements for the amide bond "B-region" moiety of capsaicin have been synthesized, including vanillylamides and esters, homovanillic acid amides and esters, ureas, and thioureas. These have been tested in an in vitro assay for agonism (45Ca2+ influx i...
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| Veröffentlicht in: | Journal of medicinal chemistry 1993-08, Vol.36 (16), p.2373-2380 |
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| container_end_page | 2380 |
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| container_issue | 16 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 36 |
| creator | Walpole, Christopher S. J Wrigglesworth, Roger Bevan, Stuart Campbell, Elizabeth A Dray, Andy James, Iain F Masdin, Kay J Perkins, Martin N Winter, Janet |
| description | A series of compounds incorporating replacements for the amide bond "B-region" moiety of capsaicin have been synthesized, including vanillylamides and esters, homovanillic acid amides and esters, ureas, and thioureas. These have been tested in an in vitro assay for agonism (45Ca2+ influx into dorsal root ganglia neurones), which is predictive of analgesic activity, to investigate the requirements in this region of capsaicin for activity. N-(4-Hydroxy-3-methoxybenzyl)-N'-octylthiourea (14a) emerged as the most potent analogue (EC50 = 0.06 microM). An operational model based on multiple hydrogen-bonding interactions is proposed to explain the structure-activity profile observed. In combination with studies on the other regions of the capsaicin molecule these results describe a picture of the molecular interactions of capsaicin with its putative receptor. |
| doi_str_mv | 10.1021/jm00068a015 |
| format | Article |
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N-(4-Hydroxy-3-methoxybenzyl)-N'-octylthiourea (14a) emerged as the most potent analogue (EC50 = 0.06 microM). An operational model based on multiple hydrogen-bonding interactions is proposed to explain the structure-activity profile observed. 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In combination with studies on the other regions of the capsaicin molecule these results describe a picture of the molecular interactions of capsaicin with its putative receptor.</description><subject>Analgesics - chemistry</subject><subject>Analgesics - pharmacology</subject><subject>Animals</subject><subject>Calcium - metabolism</subject><subject>Calcium Channel Agonists - chemistry</subject><subject>Calcium Channel Agonists - pharmacology</subject><subject>Capsaicin - analogs & derivatives</subject><subject>Capsaicin - chemistry</subject><subject>Ganglia, Spinal - drug effects</subject><subject>Ganglia, Spinal - metabolism</subject><subject>Guinea Pigs</subject><subject>Ileum</subject><subject>Mice</subject><subject>Muscle Contraction - drug effects</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1993</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkDFvFDEQRi0ECkegokayUkCB9rC9a69PVCGCBBGJSBy01njtvfjYXR8ebyANvx2jO50oaGaK78030iPkOWdLzgR_sx0ZY0oD4_IBWXApWNVo1jwkC8aEqIQS9WPyBHFbsJqL-oSc6FoxrcWC_D6fYIgbpLGnHewQQhcm-jPkWwqbOAXMFLoc7kK-p4B0ind-oFBuNh5DVxg_ZXxLMae5y3Py1ZHGPLvgcUnFkq5vPYUxOE9tnBw9e1clvwlxOntKHvUwoH922Kfk64f364ur6vrz5ceL8-sK6naVK2vZqreyVUxx5Sz0buVq27jGeq6bTjFrwTWSWyUb2QIXUmpwZQIoxpq2PiUv9727FH_MHrMZA3Z-GGDycUbTypVotdIFfL0HuxQRk-_NLoUR0r3hzPy1bf6xXegXh9rZjt4d2YPeklf7vHj0v44xpO9GtXUrzfrmi1lf3fBLJr6ZT4V_teehQ7ONcyqi8b-f_wB4S5Zh</recordid><startdate>19930806</startdate><enddate>19930806</enddate><creator>Walpole, Christopher S. 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J ; Wrigglesworth, Roger ; Bevan, Stuart ; Campbell, Elizabeth A ; Dray, Andy ; James, Iain F ; Masdin, Kay J ; Perkins, Martin N ; Winter, Janet</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a379t-bb09fb5760616dbafd9d3b4d4be184c60bbad451b65457a12558ad255aa600473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1993</creationdate><topic>Analgesics - chemistry</topic><topic>Analgesics - pharmacology</topic><topic>Animals</topic><topic>Calcium - metabolism</topic><topic>Calcium Channel Agonists - chemistry</topic><topic>Calcium Channel Agonists - pharmacology</topic><topic>Capsaicin - analogs & derivatives</topic><topic>Capsaicin - chemistry</topic><topic>Ganglia, Spinal - drug effects</topic><topic>Ganglia, Spinal - metabolism</topic><topic>Guinea Pigs</topic><topic>Ileum</topic><topic>Mice</topic><topic>Muscle Contraction - drug effects</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Walpole, Christopher S. 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| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1993-08, Vol.36 (16), p.2373-2380 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | ACS Publications; MEDLINE |
| subjects | Analgesics - chemistry Analgesics - pharmacology Animals Calcium - metabolism Calcium Channel Agonists - chemistry Calcium Channel Agonists - pharmacology Capsaicin - analogs & derivatives Capsaicin - chemistry Ganglia, Spinal - drug effects Ganglia, Spinal - metabolism Guinea Pigs Ileum Mice Muscle Contraction - drug effects Structure-Activity Relationship |
| title | Analogs of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 2. The amide bond "B-region" |
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