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Synthesis, Rotamer Orientation, and Calcium Channel Modulation Activities of Alkyl and 2-Phenethyl 1,4-Dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates

A group of racemic alkyl and 2-phenethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates (13a − q) was prepared using a modified Hantzsch reaction that involved the condensation of a 3- or 6-substituted-2-pyridinecarboxaldehyde (7a − j) with an alkyl or 2-ph...

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Published in:Journal of medicinal chemistry 1998-05, Vol.41 (11), p.1827-1837
Main Authors: Iqbal, Nadeem, Akula, Murthy R, Vo, Dean, Matowe, Wandikayi C, McEwen, Carol-Anne, Wolowyk, Michael W, Knaus, Edward E
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description A group of racemic alkyl and 2-phenethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates (13a − q) was prepared using a modified Hantzsch reaction that involved the condensation of a 3- or 6-substituted-2-pyridinecarboxaldehyde (7a − j) with an alkyl or 2-phenethyl 3-aminocrotonate (11a − d) and nitroacetone (12). Nuclear Overhauser (NOE) studies indicated there is a significant rotamer fraction in solution where the pyridyl nitrogen is oriented above the 1,4-dihydropyridine ring, irrespective of whether a substituent is located at the 3- or 6-position. A potential H-bonding interaction between the pyridyl nitrogen free electron pair and the suitably positioned 1,4-dihydropyridine NH moiety may stablize this rotamer orientation. In vitro calcium channel antagonist and agonist activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays, respectively. Compounds having an i-Pr ester substituent acted as dual cardioselective calcium channel agonists (GPLA)/smooth muscle-selective calcium channel antagonists (GPILSM), except for the C-4 3-nitro-2-pyridyl compound which exhibited an antagonist effect on both GPLA and GPILSM. In contrast, the compounds with a phenethyl ester group, which exhibited antagonist activity (IC50 = 10-5−10-7 M range) on GPILSM, were devoid of cardiac agonist activity on GPLA. Structure−activity relationships showing the effect of a substituent (Me, CF3, Cl, NO2, Ph) at the 3- or 6-position of a C-4 2-pyridyl moiety and a variety of ester substituents (Me, Et, i-Pr, PhCH2CH2-) upon calcium channel modulation are described. Compounds possessing a 3- or 6-substituted-2-pyridyl moiety, in conjuction with an i-Pr ester substituent, are novel 1,4-dihydropyridine calcium channel modulators that offer a new drug design approach directed to the treatment of congestive heart failure and may also be useful as probes to study the structure−function relationships of calcium channels.
doi_str_mv 10.1021/jm970529f
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Nuclear Overhauser (NOE) studies indicated there is a significant rotamer fraction in solution where the pyridyl nitrogen is oriented above the 1,4-dihydropyridine ring, irrespective of whether a substituent is located at the 3- or 6-position. A potential H-bonding interaction between the pyridyl nitrogen free electron pair and the suitably positioned 1,4-dihydropyridine NH moiety may stablize this rotamer orientation. In vitro calcium channel antagonist and agonist activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays, respectively. Compounds having an i-Pr ester substituent acted as dual cardioselective calcium channel agonists (GPLA)/smooth muscle-selective calcium channel antagonists (GPILSM), except for the C-4 3-nitro-2-pyridyl compound which exhibited an antagonist effect on both GPLA and GPILSM. In contrast, the compounds with a phenethyl ester group, which exhibited antagonist activity (IC50 = 10-5−10-7 M range) on GPILSM, were devoid of cardiac agonist activity on GPLA. Structure−activity relationships showing the effect of a substituent (Me, CF3, Cl, NO2, Ph) at the 3- or 6-position of a C-4 2-pyridyl moiety and a variety of ester substituents (Me, Et, i-Pr, PhCH2CH2-) upon calcium channel modulation are described. Compounds possessing a 3- or 6-substituted-2-pyridyl moiety, in conjuction with an i-Pr ester substituent, are novel 1,4-dihydropyridine calcium channel modulators that offer a new drug design approach directed to the treatment of congestive heart failure and may also be useful as probes to study the structure−function relationships of calcium channels.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm970529f</identifier><identifier>PMID: 9599233</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Atrial Function ; Biological and medical sciences ; Calcium Channel Agonists - chemical synthesis ; Calcium Channel Agonists - chemistry ; Calcium Channel Agonists - pharmacology ; Calcium Channel Blockers - chemical synthesis ; Calcium Channel Blockers - chemistry ; Calcium Channel Blockers - pharmacology ; Calcium Channels - drug effects ; Cardiovascular system ; congestive heart failure ; Guinea Pigs ; Heart Atria - drug effects ; Hydrogen Bonding ; Ileum - drug effects ; Ileum - physiology ; In Vitro Techniques ; Medical sciences ; Miscellaneous ; Muscle Contraction - drug effects ; Muscle, Smooth - drug effects ; Muscle, Smooth - physiology ; Myocardial Contraction - drug effects ; Pharmacology. Drug treatments ; pyridinecarboxylates ; Pyridines - chemical synthesis ; Pyridines - chemistry ; Pyridines - pharmacology ; Stereoisomerism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1998-05, Vol.41 (11), p.1827-1837</ispartof><rights>Copyright © 1998 American Chemical Society</rights><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a474t-ee1f11bd840403e595e18e2f1d4c493666598e426ad6b20aac0a9496a7e8d79c3</citedby><cites>FETCH-LOGICAL-a474t-ee1f11bd840403e595e18e2f1d4c493666598e426ad6b20aac0a9496a7e8d79c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=2262068$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9599233$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Iqbal, Nadeem</creatorcontrib><creatorcontrib>Akula, Murthy R</creatorcontrib><creatorcontrib>Vo, Dean</creatorcontrib><creatorcontrib>Matowe, Wandikayi C</creatorcontrib><creatorcontrib>McEwen, Carol-Anne</creatorcontrib><creatorcontrib>Wolowyk, Michael W</creatorcontrib><creatorcontrib>Knaus, Edward E</creatorcontrib><title>Synthesis, Rotamer Orientation, and Calcium Channel Modulation Activities of Alkyl and 2-Phenethyl 1,4-Dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A group of racemic alkyl and 2-phenethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates (13a − q) was prepared using a modified Hantzsch reaction that involved the condensation of a 3- or 6-substituted-2-pyridinecarboxaldehyde (7a − j) with an alkyl or 2-phenethyl 3-aminocrotonate (11a − d) and nitroacetone (12). Nuclear Overhauser (NOE) studies indicated there is a significant rotamer fraction in solution where the pyridyl nitrogen is oriented above the 1,4-dihydropyridine ring, irrespective of whether a substituent is located at the 3- or 6-position. A potential H-bonding interaction between the pyridyl nitrogen free electron pair and the suitably positioned 1,4-dihydropyridine NH moiety may stablize this rotamer orientation. In vitro calcium channel antagonist and agonist activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays, respectively. Compounds having an i-Pr ester substituent acted as dual cardioselective calcium channel agonists (GPLA)/smooth muscle-selective calcium channel antagonists (GPILSM), except for the C-4 3-nitro-2-pyridyl compound which exhibited an antagonist effect on both GPLA and GPILSM. In contrast, the compounds with a phenethyl ester group, which exhibited antagonist activity (IC50 = 10-5−10-7 M range) on GPILSM, were devoid of cardiac agonist activity on GPLA. Structure−activity relationships showing the effect of a substituent (Me, CF3, Cl, NO2, Ph) at the 3- or 6-position of a C-4 2-pyridyl moiety and a variety of ester substituents (Me, Et, i-Pr, PhCH2CH2-) upon calcium channel modulation are described. Compounds possessing a 3- or 6-substituted-2-pyridyl moiety, in conjuction with an i-Pr ester substituent, are novel 1,4-dihydropyridine calcium channel modulators that offer a new drug design approach directed to the treatment of congestive heart failure and may also be useful as probes to study the structure−function relationships of calcium channels.</description><subject>Animals</subject><subject>Atrial Function</subject><subject>Biological and medical sciences</subject><subject>Calcium Channel Agonists - chemical synthesis</subject><subject>Calcium Channel Agonists - chemistry</subject><subject>Calcium Channel Agonists - pharmacology</subject><subject>Calcium Channel Blockers - chemical synthesis</subject><subject>Calcium Channel Blockers - chemistry</subject><subject>Calcium Channel Blockers - pharmacology</subject><subject>Calcium Channels - drug effects</subject><subject>Cardiovascular system</subject><subject>congestive heart failure</subject><subject>Guinea Pigs</subject><subject>Heart Atria - drug effects</subject><subject>Hydrogen Bonding</subject><subject>Ileum - drug effects</subject><subject>Ileum - physiology</subject><subject>In Vitro Techniques</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Muscle Contraction - drug effects</subject><subject>Muscle, Smooth - drug effects</subject><subject>Muscle, Smooth - physiology</subject><subject>Myocardial Contraction - drug effects</subject><subject>Pharmacology. Drug treatments</subject><subject>pyridinecarboxylates</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>Stereoisomerism</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><recordid>eNqFkctuEzEUhkcIVEJhwQMgeUERlWLwfcbLKFxFUQstQmIzcuwzitMZT7A9qPNuPBxDEmWFxMqX7_Px0fmL4iklryhh9PWm0yWRTDf3ihmVjGBREXG_mBHCGGaK8YfFo5Q2hBBOGT8pTrTUmnE-K35fjyGvIfk0R1_7bDqI6DJ6CNlk34c5MsGhpWmtHzq0XJsQoEWfeze0O44WNvtfPntIqG_Qor0d290Thq_WECCvpzOdC_zGr0cXe8zmCjvf7QDmOPg8XQr8kmPUR6RwGlYp-zxkcJjh7Ri9G9tzLPdbH8CauOrvxul7SI-LB41pEzw5rKfFt3dvb5Yf8MXl-4_LxQU2ohQZA9CG0pWrBBGEg9QSaAWsoU5YoblSSuoKBFPGqRUjxlhitNDKlFC5Ult-WrzY193G_ucAKdedTxba1gToh1SXutKcE_ZfkZZKSqHkJJ7vRRv7lCI09Tb6zsSxpqT-G2l9jHRynx2KDqsO3NE8ZDjx5wdukjVtE02wPh01NuVPVDVpeK_5lOHuiE28rVXJS1nfXF3Xn8ov32W1_FGryT_b-8ametMPMUwj_kd7fwAX5cQj</recordid><startdate>19980521</startdate><enddate>19980521</enddate><creator>Iqbal, Nadeem</creator><creator>Akula, Murthy R</creator><creator>Vo, Dean</creator><creator>Matowe, Wandikayi C</creator><creator>McEwen, Carol-Anne</creator><creator>Wolowyk, Michael W</creator><creator>Knaus, Edward E</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>7QP</scope><scope>7X8</scope></search><sort><creationdate>19980521</creationdate><title>Synthesis, Rotamer Orientation, and Calcium Channel Modulation Activities of Alkyl and 2-Phenethyl 1,4-Dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates</title><author>Iqbal, Nadeem ; Akula, Murthy R ; Vo, Dean ; Matowe, Wandikayi C ; McEwen, Carol-Anne ; Wolowyk, Michael W ; Knaus, Edward E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a474t-ee1f11bd840403e595e18e2f1d4c493666598e426ad6b20aac0a9496a7e8d79c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Animals</topic><topic>Atrial Function</topic><topic>Biological and medical sciences</topic><topic>Calcium Channel Agonists - chemical synthesis</topic><topic>Calcium Channel Agonists - chemistry</topic><topic>Calcium Channel Agonists - pharmacology</topic><topic>Calcium Channel Blockers - chemical synthesis</topic><topic>Calcium Channel Blockers - chemistry</topic><topic>Calcium Channel Blockers - pharmacology</topic><topic>Calcium Channels - drug effects</topic><topic>Cardiovascular system</topic><topic>congestive heart failure</topic><topic>Guinea Pigs</topic><topic>Heart Atria - drug effects</topic><topic>Hydrogen Bonding</topic><topic>Ileum - drug effects</topic><topic>Ileum - physiology</topic><topic>In Vitro Techniques</topic><topic>Medical sciences</topic><topic>Miscellaneous</topic><topic>Muscle Contraction - drug effects</topic><topic>Muscle, Smooth - drug effects</topic><topic>Muscle, Smooth - physiology</topic><topic>Myocardial Contraction - drug effects</topic><topic>Pharmacology. Drug treatments</topic><topic>pyridinecarboxylates</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - pharmacology</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Iqbal, Nadeem</creatorcontrib><creatorcontrib>Akula, Murthy R</creatorcontrib><creatorcontrib>Vo, Dean</creatorcontrib><creatorcontrib>Matowe, Wandikayi C</creatorcontrib><creatorcontrib>McEwen, Carol-Anne</creatorcontrib><creatorcontrib>Wolowyk, Michael W</creatorcontrib><creatorcontrib>Knaus, Edward E</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>Calcium &amp; Calcified Tissue Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Iqbal, Nadeem</au><au>Akula, Murthy R</au><au>Vo, Dean</au><au>Matowe, Wandikayi C</au><au>McEwen, Carol-Anne</au><au>Wolowyk, Michael W</au><au>Knaus, Edward E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis, Rotamer Orientation, and Calcium Channel Modulation Activities of Alkyl and 2-Phenethyl 1,4-Dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1998-05-21</date><risdate>1998</risdate><volume>41</volume><issue>11</issue><spage>1827</spage><epage>1837</epage><pages>1827-1837</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A group of racemic alkyl and 2-phenethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates (13a − q) was prepared using a modified Hantzsch reaction that involved the condensation of a 3- or 6-substituted-2-pyridinecarboxaldehyde (7a − j) with an alkyl or 2-phenethyl 3-aminocrotonate (11a − d) and nitroacetone (12). Nuclear Overhauser (NOE) studies indicated there is a significant rotamer fraction in solution where the pyridyl nitrogen is oriented above the 1,4-dihydropyridine ring, irrespective of whether a substituent is located at the 3- or 6-position. A potential H-bonding interaction between the pyridyl nitrogen free electron pair and the suitably positioned 1,4-dihydropyridine NH moiety may stablize this rotamer orientation. In vitro calcium channel antagonist and agonist activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays, respectively. Compounds having an i-Pr ester substituent acted as dual cardioselective calcium channel agonists (GPLA)/smooth muscle-selective calcium channel antagonists (GPILSM), except for the C-4 3-nitro-2-pyridyl compound which exhibited an antagonist effect on both GPLA and GPILSM. In contrast, the compounds with a phenethyl ester group, which exhibited antagonist activity (IC50 = 10-5−10-7 M range) on GPILSM, were devoid of cardiac agonist activity on GPLA. Structure−activity relationships showing the effect of a substituent (Me, CF3, Cl, NO2, Ph) at the 3- or 6-position of a C-4 2-pyridyl moiety and a variety of ester substituents (Me, Et, i-Pr, PhCH2CH2-) upon calcium channel modulation are described. Compounds possessing a 3- or 6-substituted-2-pyridyl moiety, in conjuction with an i-Pr ester substituent, are novel 1,4-dihydropyridine calcium channel modulators that offer a new drug design approach directed to the treatment of congestive heart failure and may also be useful as probes to study the structure−function relationships of calcium channels.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>9599233</pmid><doi>10.1021/jm970529f</doi><tpages>11</tpages></addata></record>
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subjects Animals
Atrial Function
Biological and medical sciences
Calcium Channel Agonists - chemical synthesis
Calcium Channel Agonists - chemistry
Calcium Channel Agonists - pharmacology
Calcium Channel Blockers - chemical synthesis
Calcium Channel Blockers - chemistry
Calcium Channel Blockers - pharmacology
Calcium Channels - drug effects
Cardiovascular system
congestive heart failure
Guinea Pigs
Heart Atria - drug effects
Hydrogen Bonding
Ileum - drug effects
Ileum - physiology
In Vitro Techniques
Medical sciences
Miscellaneous
Muscle Contraction - drug effects
Muscle, Smooth - drug effects
Muscle, Smooth - physiology
Myocardial Contraction - drug effects
Pharmacology. Drug treatments
pyridinecarboxylates
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - pharmacology
Stereoisomerism
Structure-Activity Relationship
title Synthesis, Rotamer Orientation, and Calcium Channel Modulation Activities of Alkyl and 2-Phenethyl 1,4-Dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates
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