Serotonin isosterism

Bischler-Napieralski reactions, 4, 279 carboline synthesis from, 4, 516 Mannich-type reactions, 4, 279 sulfur isosteres, biological activity, 4, 913 synthesis, 4, 337, 913 Tryptophan biosynthesis, 1, 264 carboline synthesis from, 4, 516 molecular structure, 4, 162 Tryptophan hydroxylase in serotonin biosynthesis, 1, 261 Tryptophan oxygenase... 

Similarly, Carroll et al. (176)reported that the 1,2,4-oxadiazoles (e.g., 37) that are bio-isosteres of ester groups, are potent cocaine analogs. Compound (37) had low nanomolar affinity for the dopamine uptake transporter with greater than 100-fold selectivity for the dopamine transporter over the norepinephrine and serotonin transporters. 

Loratadine, where the lipophilic N-methyl group of azatidine (No. 20, Fig. 13-1) has been exchanged for the much more hydrophilic carbamate, is largely devoid of CNS activity and has been shown to be a nonsedating antihistamine. As azatidine, this drug is also isosterically related to cyproheptadine (Chapter 12), which is also a serotonin antagonist, in addition to being clinically useful as an antihistamine. 

Figure 21.17 shows two tricyclic serotonin/NE reuptake inhibitors. One is an analogue of imipramine, and the second is an isostere of doxepin. 

The role of serotonin (5-HT) in the cardiovascular system is also an active subject of investigation. Synthesis of the thiophene isosteres of ketanserin shows that the thieno[3,2- /] isomer (39) is 4-fold more selective for 5-HT2 vs. 5-HTia or a receptors than is ketanserin <91EJM807>. Tibalosine (CP 804 S, (40)) is a highly selective a 1-adrenoceptor antagonist which is significantly less potent than prazosin <83MI 212-01 >. Compound (41) is more than 100 times more selective than atenolol... 

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