Advances toward new antidepressants beyond SSRIs: 1-Aryloxy-3-piperidinylpropan-2-ols with dual 5-HT 1A receptor antagonism/SSRI activities. Part 5 Kumiko Takeuchi, * Todd J. Kohn, Nicholas A. Honigschmidt, Vincent P. Rocco, Patrick G. Spinazze, Susan K. Hemrick-Luecke, Linda K. Thompson, David C. Evans, Kurt Rasmussen, Deanna Koger, David Lodge, Laura J. Martin, Janice Shaw, Penny G. Threlkeld and David T. Wong Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA Received 26 September 2005; revised 31 October 2005; accepted 3 November 2005 Available online 17 November 2005 Dedicated to the memory of David W. Robertson, mentor, colleague and friend. Abstract—A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT 1A receptor antagonism and serotonin reup- take inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinities at the 5-HT 1A receptor and serotonin reuptake site in vitro. In vivo evaluation of this series of compounds demon- strated elevated extracellular serotonin levels from the basal and quick recovery of neuron firing that was presumably suppressed by the initial acute activation of 5-HT 1A somatodendritic autoreceptors. Ó 2005 Elsevier Ltd. All rights reserved. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) have become a standard treatment over the past decade because of their safety profile and fewer side effects than the older tricyclic antidepressants. In spite of their wide acceptance and over a decade of treatment of depres- sion, however, the need for the new generation of more efficacious antidepressant therapies with faster onset of action and a more favorable side-effect profile is now widely recognized because of their drawbacks and limited benefits. 1 Major drawbacks of SSRIs in the pharmacological treatment of depression are a latency in the onset of clinically meaningful effects for at least 3–4 weeks and the lack of consistent response in 30–40% of refractory patients. Furthermore, adverse events such as sexual dysfunction, gastrointestinal intol- erance, and activating effects (nervousness, anxiety, and insomnia) are associated with all available SSRIs and remain as considerable barriers to effective therapy. Finding the next generation of antidepressants with a new mechanism of action or a combination therapy with an SSRI has spurred a flurry of research efforts in order to accelerate the onset of effective antidepres- sant activity, while offsetting the undesirable side effects. 2 One hypothesis for the delayed onset of therapeutic ben- efits by SSRIs is that the initial SSRI-induced increase in extracellular 5-HT activates somatodendritic 5-HT 1A autoreceptors, which in turn inhibit the firing rate of the 5-HT neurons and limit the rise in extracellular 5-HT. 3,4 With chronic SSRI treatment it is thought that the autoreceptors desensitize, allowing the serotonergic neurons to resume their normal firing rate and enabling extracellular levels of 5-HT to rise to levels sufficient to achieve antidepressant effects. Co-administration of a 5-HT 1A receptor antagonist and an SSRI has been shown to accelerate antidepressant effects by several groups, 5–8 although the unsuccessful results are also reported. 9,10 A concept of developing a dual-acting agent blocking both the 5-HT 1A receptor and the 5-HT reuptake sites in a single molecule (5-HT1A/SSRI) has emerged. 11 0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2005.11.007 Keywords: 5-HT 1A /SSRI; Serotonin; 5- HT 1A receptor antagonist; Selective serotonin reuptake inhibitor; Antidepressants; 1-Aryloxy-3- piperidinylpropan-2-ols. * Corresponding author. Tel.: +1 317 276 6771; fax: +1 317 433 0715; e-mail: ktak@Lilly.com Bioorganic & Medicinal Chemistry Letters 16 (2006) 2347–2351