1-[2-Methoxy-5-(3-phenylpropyl)]-2-aminopropane Unexpectedly Shows 5-HT_2A Serotonin Receptor Affinity and Antagonist Character

Abstract

Certain phenylethylamines, such as 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB; 1a), are high-affinity 5-HT(2) agonists. Previous structure-affinity studies have concluded that both the 2,5-dimethoxy substitution pattern and the nature of substituents at the 4-position are important determinants of high affinity. We recently demonstrated that replacement of the bromo group of DOB with a 3-(phenyl)propyl substituent results in retention of affinity and that, counter to established structure-affinity relationships, the 2,5-dimethoxy substitution pattern is no longer a requirement for the binding. The present investigation extends these findings by examining a series of analogues, 3, lacking a 5-methoxy group. It was additionally found that 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) binds at 5-HT(2A) receptors with high affinity (K(i) = 13 nM) and possesses 5-HT(2A) antagonist character. Thus, not only is the 2,5-dimethoxy substitution pattern 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 required. Striking differences in the 5-HT(2A) binding requirements of the present compounds as compared to DOB-like agents suggest multiple substituent-dependent modes of binding.

Structure–activity relationships of serotonin 5‐HT2A agonists

“…For example, removal of the 5-methoxy group, and moving the alkyl substituent from the 4-to the 5-position, gave a high affinity antagonist. 77 The correlation between lipophilicity of the 4-substituent as well as limitations on the length and bulk of the substituent are consistent with the presence of a complementary hydrophobic region within the 5-HT 2A receptor. Although the location of this putative hydrophobic region has not yet been elucidated, it is evident from simulated docking studies 78,79 that it must lie somewhere within transmembrane helices 5 and/or 6.…”

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

“…Furthermore, compound 5b and 6 have about the same binding affinity as 4 (K i ¼ 5920 and 5360 nm vs. 6720 nm [32]). It must be kept in mind, however, that the binding scheme shown in Fig.…”

“…The amine 6 was prepared according to the the method described by Rangisetty et al [32] with some modifications of the reaction conditions. The introduction of the trifluoromethylsulfonyl (Tf) group into 4-hydroxy-2-methoxybenzaldehyde (9; Scheme 2) could be performed in high yield using 4-nitrophenyl triflate (easily prepared according to the method of Zhu et al [34] [35], but also commercially available; e.g., Aldrich) in DMF in the presence of K 2 CO 3 at room temperature.…”

“…The yield of 10 was 97%, and no chromatographic purification was necessary. When the introduction of the Tf group was performed using Tf 2 O in CH 2 Cl 2 /pyridine, the yield was only 47% [32]. The Suzuki protocol described above was applied to 10 and worked as well for the preparation of compound 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].…”