Novel benzofuran derivatives with dual 5-HT1A receptor and serotonin transporter affinity.

Several benzofuran derivatives linked to a 3-indoletetrahydropyridine through an alkyl chain were prepared and evaluated for serotonin transporter and 5-HT(1A) receptor affinities. Their design, synthesis and structure-activity relationships are described.

Studies toward the discovery of the next generation of antidepressants. Part 5: 3,4-Dihydro-2H-benzo[1,4]oxazine derivatives with dual 5-HT1A receptor and serotonin transporter affinity.

The design, synthesis, and structure-activity relationship of two novel classes of benzoxazine derivatives with dual selective serotonin reuptake inhibitors and 5-HT(1A) receptor activities are described.

Novel aryloxy-8-azabicyclo[3.2.1]oct-3-enes with 5-HT transporter and 5-HT1A affinity.

Joining aryl 8-azabicyclo[3.2.1]oct-3-enes with aryloxyethanes and aryloxypropanes produces novel series of compounds 11 and 12 with potent 5-HT-T affinity and moderately potent 5-HT(1A) affinity. Moreover, several of these compounds possess functional 5-HT(1A) antagonism. Optimal compounds are, 4-indolyloxyethane 21, 4-indolyloxypropanes 25, and 27, which possess potent 5-HT-T affinity (5-HT-T K(i): 21: 1.2nM, 25: 0.54nM, 27: 0.38nM) and good 5-HT(1A) affinity/antagonism (5-HT(1A)K(i), [(35)S]GTPgammaS: E(max) (%): 21: 111.1nM, 0%; 25: 173.2nM, 0%; 27: 107nM, 0%).

Studies toward the discovery of the next generation of antidepressants. 3. Dual 5-HT1A and serotonin transporter affinity within a class of N-aryloxyethylindolylalkylamines.

N-aryloxylethylindolealkylamines (5) having dual 5-HT transporter and 5-HT(1A) affinity are described. These compounds represent truncated analogues of our previously reported piperidinyl derivatives (3). Compounds in this investigation were found to have more similar affinities and functional activities for the 5-HT(1A) receptor and 5-HT transporter. Though 5-HT(1A) antagonism is not consistently observed throughout series 5, several molecular features were found to be essential to obtain high and balanced activities. The proper placement of a heteroatom in the aryl ring and the length of the linkage used to tether the indole moiety had significant influence on 5-HT(1A) and 5-HT transporter affinities. Introduction of a halogen into the aryl ring usually lowered intrinsic activity and in some cases led to full 5-HT(1A) antagonists. Compounds 33 and 34 were observed to be full 5-HT(1A) antagonists with K(i) values of approximately 30 nM for the 5-HT(1A) receptor and K(i) values of 5 and 0.5 nM for the 5-HT transporter, respectively. Unfortunately, similar to our previous series (3), compounds in this report also had high affinity for the alpha(1) receptor.

Modulation of selective serotonin reuptake inhibitor and 5-HT1A antagonist activity in 8-aza-bicyclo[3.2.1]octane derivatives of 2,3-dihydro-1,4-benzodioxane.

2,3-Dihydro-1,4-benzodioxanes with aryl 8-aza-bicyclo[3.2.1]oct-3-ene attachments 2 produce compounds with potent 5-HT-T affinity, and weak 5-HT(1A) affinity and alpha(1) affinity. This compares with 2,3-dihydro-1,4-benzodioxanes containing 8-aza-bicyclo[3.2.1] octan-3-ol attachments 4 which possess potent 5-HT(1A) affinity, moderate to good selectivity over alpha(1) and little 5-HT-T affinity. A 3-benzothiophene analogue of 4 (30) was synthesized which possesses potent 5-HT(1A) affinity and especially good selectivity over both alpha(1) and 5-HT-T.

Studies toward the discovery of the next generation of antidepressants. Part 2: incorporating a 5-HT(1A) antagonist component into a class of serotonin reuptake inhibitors.

The design and synthesis of a novel series of indole derivatives (9) having dual 5-HT transporter reuptake and 5-HT(1A) antagonist activity are described.