ABSTRACT
A new series of epiminocyclohepta[b]indoles with potent 5-HT(6) antagonist activity were discovered and optimized using in vitro protocols. One compound from this series was progressed to advanced pharmacokinetic (PK) studies followed by 5-HT(6) receptor occupancy studies. The compound was found to have excellent oral absorption, a highly favorable PK profile and demonstrated pharmacodynamic interaction with the 5-HT(6) receptor as shown by ex vivo autoradiography.
Subject(s)
Indoles/pharmacokinetics , Receptors, Serotonin/metabolism , Serotonin Antagonists , Administration, Oral , Animals , Caco-2 Cells , Humans , Indoles/administration & dosage , Indoles/chemistry , Indoles/pharmacology , Molecular Structure , Protein Binding/drug effects , Purinergic P1 Receptor Antagonists , Rats , Rats, Sprague-Dawley , Receptors, Serotonin/chemistry , Serotonin Antagonists/administration & dosage , Serotonin Antagonists/pharmacokinetics , Serotonin Antagonists/pharmacology , Structure-Activity RelationshipABSTRACT
Two series of 1-alkyl-2-aryl-4-(1-naphthoyl)pyrroles were synthesized and their affinities for the cannabinoid CB(1) and CB(2) receptors were determined. In the 2-phenyl series (5) the N-alkyl group was varied from n-propyl to n-heptyl. A second series of 23 1-pentyl-2-aryl-4-(1-naphthoyl)-pyrroles (6) was also prepared. Several compounds in both series have CB(1) receptor affinities in the 6-30nM range. The high affinities of these pyrrole derivatives relative to JWH-030 (1, R=C(5)H(11)) support the hypothesis that these pyrroles interact with the CB(1) receptor primarily by aromatic stacking.
