1-[4-(3-Phenylalkyl)phenyl]-2-aminopropanes as 5-HT_2APartial Agonists

Abstract

Phenylalkylamines such as 1-(4-bromo-2, 5-dimethoxyphenyl)-2-aminopropane (DOB; 1a) and its corresponding iodo derivative DOI (2) are commonly used 5-HT(2) serotonin agonists. Previous studies have established that the 2,5-dimethoxy substitution pattern found in these compounds is optimal for high affinity at 5-HT(2A) receptors and that substituents at the 4-position can modulate affinity over a wide range. We have previously shown, however, that when the 4-position is substituted with a 3-phenylpropyl substituent (i.e., 3), the compound binds with an affinity comparable to that of 1a but that it possesses 5-HT(2A) antagonist character. The present study examined the structure-affinity relationships of 3, and the results were very much unexpected. That is, the 2,5-dimethoxy substitution pattern of 3 is not required for high affinity. Either of the two methoxy groups can be removed without untoward effect on affinity, and relocation of the methoxy substituents actually enhances affinity by as much as an order of magnitude. None of the compounds displayed more than 20-fold selectivity for 5-HT(2A) over 5-HT(2C) receptors. In addition, several were demonstrated to act as 5-HT(2A) partial agonists. As such, the results of this study suggest that the structure-affinity relationships of phenylalkylamines as 5-HT(2A) ligands now be reinvestigated in greater detail.

4‐Aryl‐Substituted 2,5‐Dimethoxyphenethylamines: Synthesis and Serotonin 5‐HT2A Receptor Affinities

“…As soon as a further substituent is introduced, (especially) in the para-position of the second arene moiety, antagonistic binding increases dramatically, a conclusion that completely agrees with the results of Glennon and co-workers [11] [32]: i.e., as soon as larger 4'-alkyl or 4'-arylalkyl substituents are introduced into 2-phenylethylamines, the compounds behave as antagonists.…”

“…2. Influence of structural modifications upon binding affinities towards 5-HT 2 receptors (unless otherwise indicated, K i values were taken from [11] and [32]). a ) Values taken from [2].…”

“…C 4 , 3-phenylpropyl, etc.) have antagonist activity [11], but to date the transition between these structures is not well-defined.…”

“…Additionally, there may be some multidimensional phenomena (e.g., steric bulk vs. electronic properties) that make further data analysis difficult with this very limited set of compounds. Until recently, it was thought that the 2',5'-(MeO) 2 pattern was required for high affinity of phenethylamines at the serotonin 5-HT 2A receptor (reviewed in [11]). Although this pharmacophore may be necessary for agonist action, assumed to be the primary pharmacology of hallucinogenic phenethylamines [36] [37], Glennon and coworkers [11] [32] have shown that this substitution pattern is not required for highaffinity antagonists such as 13 -15.…”

“…Until recently, it was thought that the 2',5'-(MeO) 2 pattern was required for high affinity of phenethylamines at the serotonin 5-HT 2A receptor (reviewed in [11]). Although this pharmacophore may be necessary for agonist action, assumed to be the primary pharmacology of hallucinogenic phenethylamines [36] [37], Glennon and coworkers [11] [32] have shown that this substitution pattern is not required for highaffinity antagonists such as 13 -15. In the series of compounds lacking the 5'-MeO substituent, biphenyl compound 4 was investigated [32].…”