A structure-affinity study of the binding of 4-substituted analogs of 1-(2,5-dimethoxyphenyl)-2-aminopropane at 5-HT2 serotonin receptors

Abstract

With [3H]ketanserin as the radioligand, structure-affinity relationships (SAFIRs) for binding at central 5-HT2 serotonin receptors (rat frontal cortex) were examined for a series of 27 4-substituted 1-(2,5-dimethoxyphenyl)-2-aminopropane derivatives (2,5-DMAs). The affinity (Ki values) ranged over a span of several orders of magnitude. It appears that the lipophilic character of the 4-position substituent plays a major role in determining the affinity of these agents for 5-HT2 receptors, 2,5-DMAs with polar 4-substituents (e.g. OH, NH2, COOH) display a very low affinity (Ki greater than 25,000 nM) for these receptors, whereas those with lipophilic functions display a significantly higher affinity. The results of these studies prompted us to synthesize and evaluate examples of newer lipophilic derivatives and several of these (e.g. n-hexyl, n-octyl) bind with very high (Ki values = 2.5 and 3 nM, respectively) affinities at central 5-HT2 sites. Although, 2,5-DMAs are generally considered to be 5-HT2 agonists, preliminary studies with isolated rat thoracic aorta suggest that some of the more lipophilic derivatives (e.g. the n-hexyl and n-octyl derivatives) are 5-HT2 antagonists.

Structure–activity relationships of serotonin 5‐HT2A agonists

“…68 By contrast, polar 4-substituents such as OH, NH 2 , and COOH gave compounds with very low affinity (K i > 25,000 nM). 69 The latter study also examined compounds with very long lipophilic 4-substituents such as n-hexyl and n-octyl, which had high affinities at […”

Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5‐HT2A Receptors

“…The structure-activity relationships (SAR) have been extensively studied generating a vast number of phenylalkylamines with 5-HT 2A binding potential and functional activity. [64][65][66][67] The purpose of this review is to summarize the SAR of the phenylalkylamines as agonist ligands for the 5-HT 2A receptor, focusing on subtype and function selectivity. Signaling pathways, pharmacological methods, site-directed mutagenesis and molecular modeling studies relevant for 5-HT 2A receptor research are described.…”

“…After in vitro testing, these derivatives were found to act as 5-HT 2 receptor antagonists. [67] Using [ 125 I]DOI labeled human receptor data, the highest binding affinity at 5-HT 2A receptors was found for the 4-nhexyl analogue DOHx (21, K i = 0.1 nm), followed by the 4-benzyl analogue DOBz (22, K i = 0.4 nm), DOB (16, K i = 0.6 nm), DOI (17, K i = 0.7 nm), and the 4-n-propyl analogue DOPR (23, K i = 0.9 nm). [63] Continuing this line of reasoning, the 4-(3-phenylpropyl) derivative 26 was expected to have an antagonist profile.…”

“…[63] Continuing this line of reasoning, the 4-(3-phenylpropyl) derivative 26 was expected to have an antagonist profile. [67] However, later work using cloned rat 5-HT 2A receptors, and [ 3 H]ketanserin as a radioligand, showed a binding affinity of K i = 30 nm for 26, comparable to the affinity of DOB (16, K i = 32 nm), and revealed a partial agonist character in a phosphoinositide (PI) hydrolysis assay. [164] Affinity studies on analogues of compound 26 revealed that the 2,5-dimethoxy substitution pattern is not optimal for 5-HT 2A receptor affinity of 4-(3-phenylpropyl)-substituted compounds.…”

“…[164,165] Polar substituents at the 4 position generally show little affinity in the phenylalkylamine series. [67] Addition of a b-methyl group to the side chain has been found to reduce in vivo activity, and this applies to b-hydroxy and b-keto groups as well. [166,167] Interestingly, certain b-methoxy-substituted phenethylamines retain some potency in humans.…”