Receptor Looking for a Therapeutic

The clinical relevance of 5-HT2C receptor editing has been linked in association studies to suicidality (Niswender et al. 2001), schizophrenia (Sodhi et al. 2001), anxiety (Hackler et al. 2006), depression (Iwamoto et al. 2005), and spatial memory (Du et al. 2007). However, these data need confirmation, as is common in the field. 5-HT2C receptors have been shown to modulate mesolimbic dopaminergic function, where they exert a tonic inhibitory influence over dopamine neurotransmission (Di Giovanni et al. 1999; Bubar and Cunningham 2007) and, therefore, the interest in this receptor as a therapeutic target for treating abuse (Bubar and Cunningham 2006). The 5-HT2C receptor is also believed to mediate, in part, the effects of antidepressants, e.g., mirtazapine or agomela-tine (Cremers et al. 2007), possibly by stimulating neurogenesis, as well as that of atypical antipsychotics (Herrick-Davis et al. 2000). 5-HT2C receptors are expressed in the amygdala, and functional magnetic resonance imaging fMRI data have demonstrated that 5-HT2C receptor agonists produce its neuronal activation (Hackler et al. 2007). Other potential indications relate to obesity and epilepsy (Tecott et al. 1995; Tecott and Abdallah 2003), but it will be a challenge to produce selective agonists for the 5-HT2C receptor (Bonhaus et al. 1997) that do not interact with the other 5-HT2 subtypes, especially 5-HT2B which has serious liabilities (see reference Fitzgerald et al. 2000).

In any case, 5-HT2C receptors have already made a relevant contribution to the modern pharmacology: The development of selective 5-HT2C receptor drugs has been pioneer in the demonstration of the capability of certain ligands to differentially activate different signal transduction pathways (mainly inositol phosphate accumulation versus arachidonic acid release) (Berg et al. 2003). This evidence has been instrumental for the concept of "ligand-dependent functional selectivity." In addition to challenging the dogma of classical pharmacology, this concept will have a clear impact on drug discovery (Millan et al. 2003).

Acknowledgments We thank the members of the JMP and DH labs (M. Rigo, R. Lehnherr, M. Girod, E. Schuepbach, D. Fehlmann), who were instrumental in training and supporting our PhD students and postdocs active in the labs in the 5-HT1C times (C. Waeber, R. Cortés, M. Dietl, A. Karpf, H. Davies, S. Srivatsa, A. Bruinvels, P. Schoeffter, H. Neijt, V. Doyle, J. Creba, I. Sahin-Erdemli), which in turn contributed in discussions, shared lab and counter spaces, and helped in membrane preparations and some other atypical experiments. We also need to thank our colleagues (G. Engel, K.H. Buchheit, R. Markstein, H. Kalkman, H.G.W.M. Boddeke, A. Enz,

A. Fargin, A.K. Dixon, A. Closse, E. Mueller-Schweinitzer, U. Ruegg, K.H. Wiederhold,

B.P. Richardson, J.R. Fozard, M.P. Seiler, G. Mengod, E. Schlicker, M. Goethert, A. Probst, D. Middlemiss as well as various members of the 5-HT receptor nomenclature committee) for help and discussing our data in a critical and constructive manner. Finally, we thank Daniel Hauser and Manfred Karobath heads of Preclinical Research at Sandoz, which supported us all along those years.

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