title: Design and synthesis of propranolol analogues as serotonergic agents.
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.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0581.
authors.forename: M E
authors.initials: ME
authors.lastname: Pierson
authors.forename: R A
authors.initials: RA
authors.lastname: Lyon
authors.forename: M
authors.initials: M
authors.lastname: Titeler
authors.forename: S B
authors.initials: SB
authors.lastname: Schulman
authors.forename: P
authors.initials: P
authors.lastname: Kowalski
authors.forename: R A
authors.initials: RA
authors.lastname: Glennon
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D003342:Corpus Striatum / Q000378:metabolism; D015195:Drug Design; D005625:Frontal Lobe / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D011433:Propranolol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D011943:Receptors, Adrenergic, beta; D011985:Receptors, Serotonin; D011433:Propranolol