BENZYLIMIDAZOLINES AS H5-HT1B 1D SEROTONIN RECEPTOR LIGANDS - A STRUCTURE-AFFINITY INVESTIGATION/

Benzylimidazolines may represent a class of 5-HT1D ligands that has ye t to be exploited. On the basis of a previous report that the 2-(subst ituted-benzyl)imidazoline alpha-adrenergic agonist oxymetazoline (8) b inds with high affinity at calf brain 5-HT1D receptors, we explored th e 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 subst ituents 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-HT1D (i.e., human 5-HT1D alpha) receptors, this modification r educed h5-HT1B (i.e., human 5-HT1D beta) receptor affinity by nearly 5 0-fold. The 2,6-dimethyl groups also contribute to binding but seem to play a greater role for h5-HT1B binding than h5-HT1D binding.With the appropriate structural modifications, several compounds were identifi ed that display 20- to >100-fold selectivity for h5-HT1D versus h5-HT1 B receptors. Preliminary functional data suggest that these compounds behave as agonists. Given that 5-HT1D agonists are currently being exp lored for their antimigraine action and that activation of h5-HT1B rec eptors might be associated with cardiovascular side effects, h5-HT1D-s elective agents may offer a new lead for the development of therapeuti cally efficacious agents.