The preparation of a series of conformationally restricted analogues of indolylurea 1, namely tetrahydropyrroloindoles and tetrahydropyrroloquinolines, is described. The binding affinities of these compounds at 5-HT2A, 5-HT2B, and 5-HT2C receptors were determined. Of these compounds, the 1,2,3,5-tetrahydropyrrolo[2,3-f]indole derivative, compound 11, was found to have high affinity for the 5-HT2C (pKI 8.0) and 5-HT2B receptors (pA2 8.5), with excellent selectivity over the 5-HT2A and various other receptors (pKI < 6). 11 is also considerably more active than 1 in both an in vitro functional model, 5-HT-stimulated phosphoinositol hydrolysis (pKB 8.8), and an in vivo functional model, mCPP-induced hypolocomotion (ID50 5.5 mg/kg po). 11 should therefore be of significant utility as a pharmacological tool to delineate the functional significance of blockade of 5-HT2B and 5-HT2C receptors.
The syntheses of benzamides containing azabicyclo[x.y.z] side chains and their 5-HT4 receptor agonist and 5-HT3 receptor antagonist properties are described. These compounds were designed to mimic higher energy conformations of quinolizidine and indolizidine. High potency was achieved for both activities although an exactly paralleling SAR was not apparent. Introduction of O and S resulted in only marginal differences in potency which was more apparent for 5-HT3 antagonism. The introduction of a methyl group alpha to the basic nitrogen resulted in a reduction in 5-HT4 receptor agonist potency. Renzapride (5f) was identified for further evaluation for which both enantiomers had an identical pharmacological profile, as did an azatricyclic 9b, which contained a combination of the steric bulk of the two separate enantiomers.
Synthesis of Bromosubstituted Butenolides 11. -Sztnznznry. Methyl 4,4'-dibromosenecioate (2) was prepared by double N-bromosuccinimide bromination of mcthyl senecioate (1) and converted to methyl 4,4'-diiodo-senecioate (3) with sodium iodide and t o 3-bromoniethyl-2-buten-4-olide (4) with aqueous hydrobromic acid. A mixture of mcthyl (2)-and (E)-4-broniosenecioate (8 and 9) yielded 3-methyl-2-butenolide ( 5 ) with aqueous hydrobroinic acid and a mixture of ( Z ) -and (E)-4-methoxy-senecioic acid (10 and 11) with incthanolic potassium hydroxide. N-Bromosuccinimide treatment of the butenolide 5 afforded 4-bronio-3-methyl-2-buten-4-olide (6) and 4,4-dibromo-3-methyl-2-butcn-4-olidc (7).Vor kurzem haben wir uber die Herstellung von einigen broni-substituierten Butenoliden aus dibromierten ungesattigten Estern und aus einfaclien Butenoliden herichtet I 11. Wir besclireiben nun die Herstellung analoger Derivate der Seneciosaure.Behandlung voii Seneciosaure-methylester (1) n i t 2 Aquiv. N-Bromsuccinimid lieferte 67% 4,4'-Dibrom-seneciosaure-methylester (2)3), der mit Natriumjodid in ilceton in 47% 4,4'-Dijod-seneciosaure-methylester (3) nnd init 48proz. Bromwasserstoffqaure in 87% 3-Rrommetliyl-2-buten-4-olid (4) umgewandelt wurde. waihrend zwei an Brom gcbundene Carbonylkolilenstoffatome schnell relaxieren sollteii ; weiterhin durfte fur die erm-ahten Saurebromide keiii I ) Post-doktoraler Mitarbeiter 1972-1973
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