Effects of polar κ receptor agonists designed for the periphery on ATP-induced Ca 2+ release from keratinocytes
In order to obtain polar κ agonists, which cannot pass the blood–brain barrier, secondary amines 3a and 3b were reductively alkylated with pyridine-3-carbaldehyde to give pyridylmethyl substituted perhydroquinoxalines 5a and 5b , respectively. Both 5a and 5b show very high κ-opioid receptor affinity...
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| Veröffentlicht in: | MedChemComm 2016, Vol.7 (2), p.317-326 |
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| creator | Galla, Fabian Bourgeois, Christian Lehmkuhl, Kirstin Schepmann, Dirk Soeberdt, Michael Lotts, Tobias Abels, Christoph Ständer, Sonja Wünsch, Bernhard |
| description | In order to obtain polar κ agonists, which cannot pass the blood–brain barrier, secondary amines
3a
and
3b
were reductively alkylated with pyridine-3-carbaldehyde to give pyridylmethyl substituted perhydroquinoxalines
5a
and
5b
, respectively. Both
5a
and
5b
show very high κ-opioid receptor affinity with
K
i
values of 0.13 nM and 3.8 nM, respectively. Moreover, they are very selective for the κ receptor. In the [
35
S]GTPγS assay, both quinoxalines reached full agonistic activity. With an EC
50
value of 34 nM,
5a
is only slightly less potent than the prototypical κ agonist U-69,593. For the determination of the log
D
values, a shake-flask method was developed, making use of quantification by mass spectrometry which requires only very small amounts of the compound ( |
| doi_str_mv | 10.1039/C5MD00414D |
| format | Article |
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3a
and
3b
were reductively alkylated with pyridine-3-carbaldehyde to give pyridylmethyl substituted perhydroquinoxalines
5a
and
5b
, respectively. Both
5a
and
5b
show very high κ-opioid receptor affinity with
K
i
values of 0.13 nM and 3.8 nM, respectively. Moreover, they are very selective for the κ receptor. In the [
35
S]GTPγS assay, both quinoxalines reached full agonistic activity. With an EC
50
value of 34 nM,
5a
is only slightly less potent than the prototypical κ agonist U-69,593. For the determination of the log
D
values, a shake-flask method was developed, making use of quantification by mass spectrometry which requires only very small amounts of the compound (<0.8 mg). According to this method, the log
D
7.4
and log
D
5.4
values of
5a
were 1.1 and −0.45, indicating very high polarity. The log
D
5.4
value was recorded due the acidic milieu of the skin. Perhydroquinoxalines
3–5
reduced the release of Ca
2+
ions into the cytoplasm after stimulation of HaCaT cells with ATP, thereby proving biological activity in human skin cells.</description><identifier>ISSN: 2040-2503</identifier><identifier>EISSN: 2040-2511</identifier><identifier>DOI: 10.1039/C5MD00414D</identifier><language>eng</language><ispartof>MedChemComm, 2016, Vol.7 (2), p.317-326</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c76D-988a426505f195d003c52f890e13455d3e945b2de3f8e69363b34975507b4cdf3</citedby><cites>FETCH-LOGICAL-c76D-988a426505f195d003c52f890e13455d3e945b2de3f8e69363b34975507b4cdf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,4009,27902,27903,27904</link.rule.ids></links><search><creatorcontrib>Galla, Fabian</creatorcontrib><creatorcontrib>Bourgeois, Christian</creatorcontrib><creatorcontrib>Lehmkuhl, Kirstin</creatorcontrib><creatorcontrib>Schepmann, Dirk</creatorcontrib><creatorcontrib>Soeberdt, Michael</creatorcontrib><creatorcontrib>Lotts, Tobias</creatorcontrib><creatorcontrib>Abels, Christoph</creatorcontrib><creatorcontrib>Ständer, Sonja</creatorcontrib><creatorcontrib>Wünsch, Bernhard</creatorcontrib><title>Effects of polar κ receptor agonists designed for the periphery on ATP-induced Ca 2+ release from keratinocytes</title><title>MedChemComm</title><description>In order to obtain polar κ agonists, which cannot pass the blood–brain barrier, secondary amines
3a
and
3b
were reductively alkylated with pyridine-3-carbaldehyde to give pyridylmethyl substituted perhydroquinoxalines
5a
and
5b
, respectively. Both
5a
and
5b
show very high κ-opioid receptor affinity with
K
i
values of 0.13 nM and 3.8 nM, respectively. Moreover, they are very selective for the κ receptor. In the [
35
S]GTPγS assay, both quinoxalines reached full agonistic activity. With an EC
50
value of 34 nM,
5a
is only slightly less potent than the prototypical κ agonist U-69,593. For the determination of the log
D
values, a shake-flask method was developed, making use of quantification by mass spectrometry which requires only very small amounts of the compound (<0.8 mg). According to this method, the log
D
7.4
and log
D
5.4
values of
5a
were 1.1 and −0.45, indicating very high polarity. The log
D
5.4
value was recorded due the acidic milieu of the skin. Perhydroquinoxalines
3–5
reduced the release of Ca
2+
ions into the cytoplasm after stimulation of HaCaT cells with ATP, thereby proving biological activity in human skin cells.</description><issn>2040-2503</issn><issn>2040-2511</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNpFkE1OwzAQhS0EElXphhN4DQr4N4mXVVp-pCJYZB859rgNpHFkh0WuxiE4E0YgmM2M3jx9enoIXVJyQwlXt5V82hAiqNicoAUjgmRMUnr6dxN-jlYxvpI0nJWlEgs0bp0DM0XsHR59rwP-_MABDIyTD1jv_dDF9LUQu_0AFrukTgfAI4RuPECYsR_wun7JusG-m2SoNGbXidCDjoBd8Ef8BkFP3eDNPEG8QGdO9xFWv3uJ6rttXT1ku-f7x2q9y0yRbzJVllqwXBLpqJI25TWSuVIRoFxIaTkoIVtmgbsScsVz3nKhCilJ0QpjHV-iqx-sCT7GAK4ZQ3fUYW4oab7bav7b4l9Ls1yH</recordid><startdate>2016</startdate><enddate>2016</enddate><creator>Galla, Fabian</creator><creator>Bourgeois, Christian</creator><creator>Lehmkuhl, Kirstin</creator><creator>Schepmann, Dirk</creator><creator>Soeberdt, Michael</creator><creator>Lotts, Tobias</creator><creator>Abels, Christoph</creator><creator>Ständer, Sonja</creator><creator>Wünsch, Bernhard</creator><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>2016</creationdate><title>Effects of polar κ receptor agonists designed for the periphery on ATP-induced Ca 2+ release from keratinocytes</title><author>Galla, Fabian ; Bourgeois, Christian ; Lehmkuhl, Kirstin ; Schepmann, Dirk ; Soeberdt, Michael ; Lotts, Tobias ; Abels, Christoph ; Ständer, Sonja ; Wünsch, Bernhard</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c76D-988a426505f195d003c52f890e13455d3e945b2de3f8e69363b34975507b4cdf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Galla, Fabian</creatorcontrib><creatorcontrib>Bourgeois, Christian</creatorcontrib><creatorcontrib>Lehmkuhl, Kirstin</creatorcontrib><creatorcontrib>Schepmann, Dirk</creatorcontrib><creatorcontrib>Soeberdt, Michael</creatorcontrib><creatorcontrib>Lotts, Tobias</creatorcontrib><creatorcontrib>Abels, Christoph</creatorcontrib><creatorcontrib>Ständer, Sonja</creatorcontrib><creatorcontrib>Wünsch, Bernhard</creatorcontrib><collection>CrossRef</collection><jtitle>MedChemComm</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Galla, Fabian</au><au>Bourgeois, Christian</au><au>Lehmkuhl, Kirstin</au><au>Schepmann, Dirk</au><au>Soeberdt, Michael</au><au>Lotts, Tobias</au><au>Abels, Christoph</au><au>Ständer, Sonja</au><au>Wünsch, Bernhard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of polar κ receptor agonists designed for the periphery on ATP-induced Ca 2+ release from keratinocytes</atitle><jtitle>MedChemComm</jtitle><date>2016</date><risdate>2016</risdate><volume>7</volume><issue>2</issue><spage>317</spage><epage>326</epage><pages>317-326</pages><issn>2040-2503</issn><eissn>2040-2511</eissn><abstract>In order to obtain polar κ agonists, which cannot pass the blood–brain barrier, secondary amines
3a
and
3b
were reductively alkylated with pyridine-3-carbaldehyde to give pyridylmethyl substituted perhydroquinoxalines
5a
and
5b
, respectively. Both
5a
and
5b
show very high κ-opioid receptor affinity with
K
i
values of 0.13 nM and 3.8 nM, respectively. Moreover, they are very selective for the κ receptor. In the [
35
S]GTPγS assay, both quinoxalines reached full agonistic activity. With an EC
50
value of 34 nM,
5a
is only slightly less potent than the prototypical κ agonist U-69,593. For the determination of the log
D
values, a shake-flask method was developed, making use of quantification by mass spectrometry which requires only very small amounts of the compound (<0.8 mg). According to this method, the log
D
7.4
and log
D
5.4
values of
5a
were 1.1 and −0.45, indicating very high polarity. The log
D
5.4
value was recorded due the acidic milieu of the skin. Perhydroquinoxalines
3–5
reduced the release of Ca
2+
ions into the cytoplasm after stimulation of HaCaT cells with ATP, thereby proving biological activity in human skin cells.</abstract><doi>10.1039/C5MD00414D</doi><tpages>10</tpages></addata></record> |
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| ispartof | MedChemComm, 2016, Vol.7 (2), p.317-326 |
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| language | eng |
| recordid | cdi_crossref_primary_10_1039_C5MD00414D |
| source | Royal Society Of Chemistry Journals 2008-; Alma/SFX Local Collection |
| title | Effects of polar κ receptor agonists designed for the periphery on ATP-induced Ca 2+ release from keratinocytes |
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