N-(phthalimidoalkyl) derivatives of serotonergic agents: a common interaction at 5-HT1A serotonin binding sites?
Several classes of agents are known to bind at central 5-HT1A serotonin sites In order to challenge the hypothesis that these agents bind in a relatively similar manner (i.e., share common aryl and terminal amine sites), we prepared N-(phthalimidobutyl) derivatives of examples of several such agents. With regard to arylpiperazines, we had previously shown that introduction of this functionality at the terminal amine is tolerated by the receptor and normally results in a significant (greater than 10-fold) enhancement in affinity. The results of the present study show that this bulky functionality is also tolerated by the receptor when incorporated into examples of all other major classes of 5-HT1A agents (e.g., 2-aminotetralin, phenylalklamine, indolylalkylamine, and (aryloxy)alkylamine derivatives). The length of the alkyl chain that separates the terminal amine from the phthalimido group is of major importance, and a four-carbon chain appears optimal. Alteration of the length of this chain can have a significant influence on affinity; decreasing the chain length from four to three carbon atoms can reduce affinity by an order of magnitude, and further shortening can have an even more pronounced effect.
Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0581.
R A
RA
Glennon
N A
NA
Naiman
M E
ME
Pierson
J D
JD
Smith
A M
AM
Ismaiel
M
M
Titeler
R A
RA
Lyon
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D066298:In Vitro Techniques; D008297:Male; D010797:Phthalimides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism
D010797:Phthalimides; D011985:Receptors, Serotonin