Abstract：
:Serotonin (5-HT) binds with nearly identical affinity at the various central 5-HT binding sites. Few agents bind with selectivity for 5-HT1A sites. The beta-adrenergic antagonist propranolol binds stereoselectively both at 5-HT1A and 5-HT1B sites (with a several-fold selectivity for the latter) and, whereas it is a 5-HT1A antagonist, it appears to be a 5-HT1B agonist. As such, it could serve as a lead compound for the development of new 5-HT1A and 5-HT1B agents. The purpose of the present study was to modify the structure of propranolol in such a manner so as to reduce its affinity for 5-HT1B and beta-adrenergic sites while, at the same time, retaining its affinity for 5-HT1A sites. Removal of the side-chain hydroxyl group of propranolol, and conversion of its secondary amine to a tertiary amine, reduced affinity for 5-HT1B and beta-adrenergic sites. In addition, shortening the side chain by one carbon atom resulted in compounds with affinity for hippocampal 5-HT1A sites comparable to that of racemic propranolol, but with a 30- to 500-fold lower affinity for 5-HT1B sites and a greater than 1000-fold lower affinity for beta-adrenergic sites. The results of these preliminary studies attest to the utility of this approach for the development of novel serotonergic agents.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Pierson ME,Lyon RA,Titeler M,Schulman SB,Kowalski P,Glennon RAdoi
10.1021/jm00124a021subject
Has Abstractpub_date
1989-04-01 00:00:00pages
859-63issue
4eissn
0022-2623issn
1520-4804journal_volume
32pub_type
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更新日期：2003-10-23 00:00:00
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更新日期：2001-06-21 00:00:00
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更新日期：1989-05-01 00:00:00
