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

With [SH]ketanserin as the radioligand, structureaffinity relationships (SAFIRs) for binding at central 5HTz serotonin receptors (rat frontal cortex) were examined for a series of 27 4-substituted 1-(2,5dimethoxypheny1)-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-HTz receptors, 2,5-DMs with polar 4-substituents (e.g. OH, NHz, COOH) display a very low affinity (Ki > 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-HTz 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. Central serotonin (5-HT) receptors can be categorized as belonging to one of three major classes: 5-HT1, 5-HT2, and 5-HT3,192 Serotonin itself is nonselective and binds at each of these neurotransmitter sites. One of the goals of our work is to develop site-selective 5-HT agonists and antagonists and, to this extent, we have demonstrated that certain 4-substituted 1-(2,5-dimethoxyphenyl)-2-aminopropane (i.e., 2,5-DMA) derivatives bind at 5-HT2 receptor sites.3 We have also found that the affinity and selectivity of these agents are significantly influenced by the nature of the 4-substituent. For example, 2,5-DMA (la) binds at 5-HT2 sites with little selectivity and with rather low affinity (Ki = 5200 nM), whereas its 4-bromo derivative DOB (lg) binds selectively and with considerably greater affinity (Ki = 40 nM).'t* Indeed, [3H]DOB is now commercially available as a radioligand for use in binding studies. In order to determine the influence of the 4substituents on binding at 5-HT2 sites, several years ago we conducted a Hansch analysis on a series of 13 derivatives of 2,5-DMA that varied in structure only at the 4p~sition.~ Preliminary results suggested that lipophilic substituents are important for affinity. We have now prepared and examined a total of 27 4-substituted derivatives of 2,5-DMA with a broader range of substituents in order to further challenge this hypothesis. We report here the synthesis and 5-HT2 binding data for the new compounds and the structure-affinity relationships (SAFIR) for the entire series. We have also found that some of the new, more lipophilic 2,5-DMA derivatives act as 5-HT2 antagonists. Chemistry A total of 21 2,5-DMA derivatives were examined in the present study; some of these compounds (i.e., la-e,g-k,m-o) are the 13 included in the original study and their syntheses have been previously The 4-chloro derivative If was synthesized according to the method of Coutts and Malicky.s Amine It was prepared by catalytic