1-[2-methoxy-5-(3-phenylpropyl)]-2-aminopropane unexpectedly shows 5-HT2A serotonin receptor affinity and antagonist character

Certain phenylethylamines, such as 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminop ropane (DOB; 1a), are high-affinity 5-HT2 agonists. Previous structure-affi nity studies have concluded that both the 2,5-dimethoxy substitution patter n and the nature of substituents at the 4-position are important determinan ts of high affinity. We recently demonstrated that replacement of the bromo group of DOB with a 3-(phenyl)propyl substituent results in retention of a ffinity and that, counter to established structure-affinity relationships, the 2,5-dimethoxy substitution pattern is no longer a requirement for the b inding. The present investigation extends these findings by examining a ser ies of analogues, 3, lacking a 5-methoxy group. It was additionally found t hat shifting the phenylalkyl substituent from the 4- to the 5-position (e.g ., 4i) also results in retention of affinity. For example, 1-(2-methoxy-5-( 3-phenylpropyl)-2-aminopropane (6; the alpha -methyl derivative of 4i) bind s at 5-HT2A receptors with high affinity (K-i = 13 nM) and possesses 5-HT2A antagonist character. Thus, not only is the 2,5-dimethoxy substitution pat tern not a requirement for the binding of certain phenylethylamines at 5-HT 2A receptors, the presence of a 4-position substituent (previously thought to serve as a modulator of affinity of DOB-like agents) is also not require d. Striking differences in the 5-HT2A binding requirements of the present c ompounds as compared to DOB-like agents suggest multiple substituent-depend ent modes of binding.