THE DEVELOPMENT OF INDOLEAMINE DERIVATIVES SELECTIVE FOR SUBTYPES OF SEROTONIN RECEPTORS (TRYPTAMINE, BASILAR ARTERY, ANTAGONIST, ERGOLINE, SYNTHESIS)
AuthorTAYLOR, ETHAN WILL.
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PublisherThe University of Arizona.
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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.
Degree ProgramPharmacology & Toxicology