Benzylimidazolines as h5-HT(1B/1D) serotonin receptor ligands: A structure-affinity investigation

Article abstract of DOI:10.1021/jm970513p

Benzylimidazolines may represent a class of 5-HT(1D) ligands that has yet to be exploited. On the basis of a previous report that the 2- (substituted-benzyl)imidazoline α-adrenergic agonist oxymetazoline (8) binds with high affinity at calf brain 5-HT(1D) receptors, we explored the structure-affinity relationships of a series of related derivatives. Each of the aromatic substituents was removed and then reinstated in a systematic manner to determine the influence of the individual substituents on binding. It was found that all of the aromatic substituents of 8 act in concert to impart high affinity. However, although the 3-hydroxy group could be removed without significantly reducing affinity for h5-HT(1D) (i.e., human 5- HT(1Dα)) receptors, this modification reduced h5-HT(1B) (i.e., human 5- HT(1Dβ)) receptor affinity by nearly 50-fold. The 2,6-dimethyl groups also contribute to binding but seem to play a greater role for h5-HT(1B) binding than h5-HT(1D) binding. With the appropriate structural modifications, several compounds were identified that display 20- to > 100-fold selectivity for h5-HT(1D) versus h5-HT(1B) receptors. Preliminary functional data suggest that these compounds behave as agonists. Given that 5-HT(1D) agonists are currently being explored for their antimigraine action and that activation of h5-HT(1B) receptors might be associated with cardiovascular side effects, h5- HT(1D)selective agents may offer a new lead for the development of therapeutically efficacious agents.