Chemical studies on serotonin analogs.

Abstract

The major focus of our research has been the design, synthesis and pharmacological evaluation of serotonin or 5-hydroxytryptamine (5-HT; 1) analogs. These include the conformationally restricted, rigid and semirigid analogs and those with a variety of different substituents, both electron donating and electron withdrawing, on the critically important indole 5-position. Two most interesting analogs in the tryptamine series are 5- carboxamidotryptamine (5-CT; 3a), a potent agonist at 5-HT₁ receptor and N,N-dipropyl- 5-carboxamido tryptamine (5-DPCT; 3b), a potent and selective agonist at the 5-HT₁ₐ receptor. We have found that this potency also extends to the semirigid analogs, 5- carboxamido-3-tetrahydropyridyl indoles (2a, 2b) (Agarwal et aI., 1993; Dahlgren et aI., 1995). In my research we decided to replace the 5-carboxyamido group by a group called the ɑ-fluoroethenyl or the ɑ-fluorovinyl group which was first proposed as an amide bond isostere in peptides (Allmendinger et aI., 1990). We synthesized 5-(ɑ-fluorovinyl)- 3-tetrahydropyridyl indoles (I, II) and 5-(a-fluorovinyl) tryptamines (III, IV) which could be potential bioisosteres of 2a, 2b, 3a and 3b. The a-fluorovinyl group was introduced on the indole 5-position using an "atypical" Heck reaction to prepare 5-(afluorovinyl) indole (5), the starting material for all the target compounds. We also performed some experiments to confirm the mechanism of the base-catalyzed direct condensation ofN-methyl-3- and -4-piperidones with indoles, a method employed for the synthesis of 3-tetrahydropyridylindoles I and II.