Development of serotonin and norepinephrine transporter inhibitor pharmacophore models: Design of selective ligands

COMP 229

Elizabeth M. Collantes,, Neuroscience Chemistry, Pfizer Inc, MS 8220 4068, 558 Eastern Point Rd, Groton, CT 06340 and Daniel F. Ortwine,, Discovery Chemistry, Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080.
Mononamine transporters, including the 5-hydroxytryptamine (5-HT; serotonin) transporter (SERT) and the noradrenaline (norepinephrine) transporter (NET), play an important role in maintaining the concentration of biogenic amine neurotransmitters in the central nervous system (CNS). Along with the dopamine transporter (DAT), SERT and NET have been implicated in the pathology of various psychological and neurological disorders but despite their clinical significance, the understanding of the structural aspects of SERT and NET and the relation to function and antagonist recognition is limited. With no reported 3D molecular structures for these transporters, there have been attempts to develop 3D structures of SERT and NET based on homology to available crystal structures of genetically- and functionally-related transporter proteins. While such models have provided insights as to the molecular mechanism of action, detailed results have been hampered by the approximations used in the homology modeling process. Conversely, the availability of a plethora of ligands has allowed the development of pharmacophore models specific to serotonin and norepinephrine reuptake inhibitors. In this study, we describe the derivation of 3D pharmacophore models rationalizing the affinity of multiple chemical series for the serotonin and norepinephrine transporters. We present their major characteristics and differences, and their use in the design of ligands targeting SERT and NET as well as design of ligands with mixed activity profiles.

Poster Session
6:00 PM-8:00 PM, Tuesday, August 18, 2009 Walter E. Washington Convention Center -- Ballroom A, Poster

8:00 PM-10:00 PM, Monday, August 17, 2009 Walter E. Washington Convention Center -- Hall D, Sci-Mix

Division of Computers in Chemistry

The 238th ACS National Meeting, Washington, DC, August 16-20, 2009