THE DEVELOPMENT OF INDOLEAMINE DERIVATIVES SELECTIVE FOR SUBTYPES OF SEROTONIN RECEPTORS (TRYPTAMINE, BASILAR ARTERY, ANTAGONIST, ERGOLINE, SYNTHESIS).

Persistent Link:
http://hdl.handle.net/10150/188104
Title:
THE DEVELOPMENT OF INDOLEAMINE DERIVATIVES SELECTIVE FOR SUBTYPES OF SEROTONIN RECEPTORS (TRYPTAMINE, BASILAR ARTERY, ANTAGONIST, ERGOLINE, SYNTHESIS).
Author:
TAYLOR, ETHAN WILL.
Issue Date:
1985
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Central serotonin (5-hydroxytryptamine, 5-HT) receptors are classified into 5-HT₁ (defined by [³H]5-HT binding) and 5-HT₂ (defined by [³H]ketanserin binding). Antagonists selective for 5-HT₁ receptors or 5-HT₁(A) and 5-HT₁(B) subtypes are currently unavailable. To develop such antagonists, a study of derivatives of tryptamine (TRYP) (which are generally selective for 5-HT₁ sites) was undertaken. For amino-N-substituted TRYPs at 5-HT₁ sites, although overall potency decreases with increased N-alkyl substituent size (up to N,N-di-iPr), discrimination between subtypes of 5-HT₁ sites increases. Compounds such as N,N-di-iPr-TRYP (DIPT) and 3-(2-morpholinoethyl)indole (MEI) recognize 30% of [³H] 5-HT binding sites with high affinity (Ki<50 nM) , the rest with low affinity (Ki >4000 nM). For both the DIPT (agonist) and MEI (antagonist) series, incorporating 5-oxy substituents resulted in rank order to overall 5-HT₁ potency of 5 - OH>MeO=5H>BzO; however, the 5-oxy compounds lost the high-affinity recognition component shown by DIPT and MEI. Incorporation of an additional hetero-aromatic moiety gave amino-N-aryl substituted TRYPs (prototype AHR 1709). These were (1) highly selective for 5-HT₁(A) sites (Ki = 10 - 200 nM) over 5-HT₁(B) sites (Ki > 3000 nM), (2) potent at the 5-HT site & (3) vascular antagonists of 5-HT. Pharmacophoric differences between 5-HT₁, 5-HT₁(A) and 5-HT₂ sites were studied with rigid analogs. Racemic partial ergolines RU 27849 and RU 28306 showed diminished potency compared to TRYPs at 5-HT₁ sites, but were equipotent to homologous TRYPs at the 5-HT₂ site. At all three sites, 3-(tetrahydropyridyl)indoles (THPIs) were the most potent rigid analogs studied. A non-ergoline-like constrained analog of TRYP was synthesized and was even less potent than RU 27849 at 5-HT₁ sites, but was 4-5 times as potent as TRYP & RU 27849 at the 5-HT₂ site. While enhancing affinity for 5-HT₁ sites, the 5-MeO group can give reduced affinity for 5-HT₂ sites, thus enhancing 5-HT₁ selectivity. 5-Unsubstituted compounds may be best for 5-HT₂ selectivity. A study of 5-HT agonists in the canine basilar artery (CBA) suggests the contraction in vitro is mediated by a receptor similar to the 5-HT₁(A) binding site; 5-HT₂ receptors may also be present. Theoretical models for the production of apparent noncompetitive antagonism to 5-HT in the CBA are also examined. Syntheses of tryptamine derivatives and a conformationally constrained analog of TRYP are described.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Serotonin.; Serotonin -- Antagonists.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmacology and Toxicology; Graduate College
Degree Grantor:
University of Arizona

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleTHE DEVELOPMENT OF INDOLEAMINE DERIVATIVES SELECTIVE FOR SUBTYPES OF SEROTONIN RECEPTORS (TRYPTAMINE, BASILAR ARTERY, ANTAGONIST, ERGOLINE, SYNTHESIS).en_US
dc.creatorTAYLOR, ETHAN WILL.en_US
dc.contributor.authorTAYLOR, ETHAN WILL.en_US
dc.date.issued1985en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractCentral serotonin (5-hydroxytryptamine, 5-HT) receptors are classified into 5-HT₁ (defined by [³H]5-HT binding) and 5-HT₂ (defined by [³H]ketanserin binding). Antagonists selective for 5-HT₁ receptors or 5-HT₁(A) and 5-HT₁(B) subtypes are currently unavailable. To develop such antagonists, a study of derivatives of tryptamine (TRYP) (which are generally selective for 5-HT₁ sites) was undertaken. For amino-N-substituted TRYPs at 5-HT₁ sites, although overall potency decreases with increased N-alkyl substituent size (up to N,N-di-iPr), discrimination between subtypes of 5-HT₁ sites increases. Compounds such as N,N-di-iPr-TRYP (DIPT) and 3-(2-morpholinoethyl)indole (MEI) recognize 30% of [³H] 5-HT binding sites with high affinity (Ki<50 nM) , the rest with low affinity (Ki >4000 nM). For both the DIPT (agonist) and MEI (antagonist) series, incorporating 5-oxy substituents resulted in rank order to overall 5-HT₁ potency of 5 - OH>MeO=5H>BzO; however, the 5-oxy compounds lost the high-affinity recognition component shown by DIPT and MEI. Incorporation of an additional hetero-aromatic moiety gave amino-N-aryl substituted TRYPs (prototype AHR 1709). These were (1) highly selective for 5-HT₁(A) sites (Ki = 10 - 200 nM) over 5-HT₁(B) sites (Ki > 3000 nM), (2) potent at the 5-HT site & (3) vascular antagonists of 5-HT. Pharmacophoric differences between 5-HT₁, 5-HT₁(A) and 5-HT₂ sites were studied with rigid analogs. Racemic partial ergolines RU 27849 and RU 28306 showed diminished potency compared to TRYPs at 5-HT₁ sites, but were equipotent to homologous TRYPs at the 5-HT₂ site. At all three sites, 3-(tetrahydropyridyl)indoles (THPIs) were the most potent rigid analogs studied. A non-ergoline-like constrained analog of TRYP was synthesized and was even less potent than RU 27849 at 5-HT₁ sites, but was 4-5 times as potent as TRYP & RU 27849 at the 5-HT₂ site. While enhancing affinity for 5-HT₁ sites, the 5-MeO group can give reduced affinity for 5-HT₂ sites, thus enhancing 5-HT₁ selectivity. 5-Unsubstituted compounds may be best for 5-HT₂ selectivity. A study of 5-HT agonists in the canine basilar artery (CBA) suggests the contraction in vitro is mediated by a receptor similar to the 5-HT₁(A) binding site; 5-HT₂ receptors may also be present. Theoretical models for the production of apparent noncompetitive antagonism to 5-HT in the CBA are also examined. Syntheses of tryptamine derivatives and a conformationally constrained analog of TRYP are described.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectSerotonin.en_US
dc.subjectSerotonin -- Antagonists.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmacology and Toxicologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.committeememberYamamura, Henryen_US
dc.contributor.committeememberDuckles, Sueen_US
dc.contributor.committeememberRemers, Williamen_US
dc.contributor.committeememberMartin, Arnolden_US
dc.identifier.proquest8603162en_US
dc.identifier.oclc696817561en_US
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