Conjugated enynes as nonaromatic catechol bioisosteres: Synthesis, bindingexperiments, and computational studies of novel dopamine receptor agonistsrecognizing preferentially the D-3 subtype

To evaluate nonaromatic catechol bioisosteres, the conformationally restrai ned enynes 1 and enediynes 2 were synthesized via palladium-catalyzed coupl ing as the key reaction step. Subsequent receptor binding studies at the do pamine receptor subtypes D-1, D-2 long, D-2 short, D-3, and D-4 showed high ly interesting binding profiles for the enynes la and 1b when compared to d opamine. At the guanine nucleotide-sensitive high-affinity binding site of the Da receptor, the target compound 1b (K-i = 5.2 nM) was 10-fold more pot ent than dopamine but less potent at the D-2 and D-4 subtypes. In contrast to dopamine the agonists la and Ib showed strong selectivity for the recept ors of the D-2 family (D-2-D-4) As far as We know, this study represents th e first report on nonaromatic dopamine agonists. Comparison of molecular el ectrostatic potentials, derived from semiempirical molecular orbital calcul ations, and lipophilicity maps was performed.