5-HTja receptor ligands

Acid-catalyzed reaction between 4-substituted 2-aminosulfonamides 215 (R = H, Me, Cl) and 2-bromomethyl-l,3-dioxolane provides access to 3-(bromomethyl)-benzo-l-thia-2,4-diazine 1,1-dioxide 216 (Equation 48). Related compounds have been used as precursors to 3-(A -alkyl) derivatives as potential ligands for and S-HTja receptors (see Section 9.05.7.7) <2005BML1185>. 

HT,b ligands. (-)-Tertatolol shows a 20 folds preference for the 5-HTja receptor and P-adrenoceptor antagonists substituted at the para-position with respect to the arylox3Tpropanol amine chain are inactive at the 5-HT b (and 5-HT,a) receptors... 

Point mutations in cloned and expressed S-HTja receptors provides new information on the molecular 5-HT2A ligand-receptor interactions. 

These compounds (MDL 28,161 and MDL 11,939) are even 3-4 times more potent and 4-27 more selective than the corresponding ketones (cf Table 3). The 2,3-dimethoxy analogue MDL 26,508 is as potent as but less selective than MDL 28,161 and MDL 11,939 [13]. MDL 11,939 is the first truly selective S-HT, ligand. Besides the high affinity for S-HTja receptors MDL 11,939 displays low or neghgible affinity for the other 5-HT receptors as well as other nemntransmitter receptors tested [14,13]. In fiinctional tests MDL 11939 behaves as an antagonist... 

Novel 5-HT2A ligands were obtained by incorporation of the tryptamine structure into a bridged y-carboline. The most potent compounds of the series are substituted on the basic nitrogen atom with a butyrophenone chain [24]. The 7S,10R enantiomer displays the highest affinity for the S-HTja receptor. The 7R,10S enantiomer is slightly less active but more selective with respect to dopamine-D2 receptors [25] (Table 10). 

At present only a small number of selective ligands for the S-HTja or S-HTjb receptor has been published. For the S-HTjc receptor these ligands are still lacking. 

Affinity of S-HTa ligands for cloned S-HTja, S-HTjb and S-HTjc receptors... 

All compounds display a weak to very weak affinity for S-HTjc receptors. Striking is the decrease in S-HTjc receptor affinity in the desfluoro-analogues (Table 3). From the series is the N-(4-phenylbutyl)-4-(benzoyl) piperidine analogue the most selective ligand (selectivity ratio S-HTjA/S-HTgc = 240), being 17... 

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