Serotonin 5-HT„ receptor

Arylpiperazines have immensely important effects on various and diverse biological targets, in particular on CNS receptors. In the case of serotonin (5-HT) receptors, compounds containing this arylpiperazine moiety represent the largest systematically studied class of 5-HTia receptor ligands [63]. Structural alterations within long-chain arylpiperazines (LCAPs) occur mainly at the two opposite ends of a molecule and have been described by many authors [64-71]. 

The 5-HT4 receptor is a member of the seven transmembrane-spanning G protein-coupled family of receptors (GPCR) and constitutes an important subtype of the class of serotonin (5-HT) receptors. Initially, the 5-HT4 receptor was characterized in the neuronal cell culture [3] of mouse colliculi and was shown to be positively coupled to adenylyl cyclase. The effect of serotonin was mimicked by the 5-HT4 receptor agonists, BIMU 1 and BIMU 8, and was blocked by the 5-HT4... 

The enantiomers of the dopaminergic, and orally active 6,7,8,9-te-trahydro-jV,A-dimethyl-3 -benz[e]indol-8-amine (54) were studied for their actions on central dopamine and serotonin (5-HT) receptors [123]. The dopaminergic effects were shown to reside in the (- -)-(/ )-enantiomer. Very interestingly, it was shown that racemic (54) and its (- -)-(i )-enantiomer possess potent central 5-HT 1A receptor stimulating properties, which was not reported originally [124]. Still another indication of the trend in DA agonist SAR towards heterocyclic bioisosteres is given by compound (55) [125]. 

Recently there has been much interest in the possible role of the family of protein kinases which translate information from the second messenger to the membrane proteins. Many of these kinases are controlled by free calcium ions within the cell. It is now established that some serotonin (5-HT) receptors, for example, are linked via G proteins to the phosphatidyl inositol pathway which, by mobilizing membrane-bound diacylglycerol and free calcium ions, can activate a specific protein kinase C. This enzyme affects the concentration of calmodulin, a calcium sequestering protein that plays a key role in many intracellular processes. 

FI6URE 2—4. G-protein-coupled serotonin (5-HT) receptors that inhibit... 

Key Words Serotonin 5-HT receptor 5-HT receptor-associated protein receptosome trafficking targeting signaling. 

Buchheit. K.-H. era/. (1995) The serotonin 5-HT receptor. 2. Structure-activity studies of the indole carbazimidamide ciass of agonists. J. Med. Chem., 38. 2331-2338. 

Nonetheless, there is a vast body of literature documenting interactions between dopamine and serotonin pathways in the brain (109-111). Clearly, however, if a drug (e.g., cocaine)releases multiple transmitters, then a behavioral interaction is not surprising. Inhibition of presynaptic reuptake of serotonin, for example, could lead to postsynaptic activation of a variety of other receptors, some of which could modulate dopamine function. In addition to potential effects on 5-HT receptors, other studies have implicated serotonin 5-HT, receptors (112), 5-HT receptors (113), and 5-HT receptors (114). 5-HT receptors can also modulate the locomotor effects of cocaine (115). 

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