Conjugated Enynes as Nonaromatic Catechol Bioisosteres:  Synthesis, Binding Experiments, and Computational Studies of Novel Dopamine Receptor Agonists Recognizing Preferentially the D₃Subtype

Abstract

To evaluate nonaromatic catechol bioisosteres, the conformationally restrained enynes 1 and enediynes 2 were synthesized via palladium-catalyzed coupling as the key reaction step. Subsequent receptor binding studies at the dopamine receptor subtypes D(1), D(2 long), D(2 short), D(3), and D(4) showed highly interesting binding profiles for the enynes 1a and 1b when compared to dopamine. At the guanine nucleotide-sensitive high-affinity binding site of the D(3) receptor, the target compound 1b (K(i) = 5.2 nM) was 10-fold more potent than dopamine but less potent at the D(2) and D(4) subtypes. In contrast to dopamine the agonists 1a and 1b showed strong selectivity for the receptors of the D(2) family (D(2)-D(4)). As far as we know, this study represents the first report on nonaromatic dopamine agonists. Comparison of molecular electrostatic potentials, derived from semiempirical molecular orbital calculations, and lipophilicity maps was performed.

18F‐Labeled FAUC 346 and BP 897 Derivatives as Subtype‐Selective Potential PET Radioligands for the Dopamine D3 Receptor

“…[ [34][35][36][37] D1 receptor affinities were measured utilizing porcine striatal membranes and the D1 selective radioligand [ 3 H]SCH 23390. [37] Because of the observation that the lead compound FAUC 346 (2 a) reveals serotonergic and adrenergic activity, 4 a-d were investigated for their potency to displace [ CoMSIA [a] exp.…”

Pharmacological Profile of 2-Bromoterguride at Human Dopamine D2, Porcine Serotonin 5-Hydroxytryptamine 2A, and α2C-Adrenergic Receptors, and Its Antipsychotic-Like Effects in Rats

“…Competition binding experiments were performed as described previously elsewhere (Hübner et al, 2000) using membrane preparations from CHO cells stably expressing either hD 2S or hD 2L receptors (Hayes et al, 1992). Assays were run with membranes at protein concentration per well of 2 mg/ml for D 2S and 4 mg/ml for D 2L and [ 2S and D 2L receptors were 0.040 and 0.12 nM; the B max values were 3470 fmol/mg and 1310 fmol/mg, respectively.…”

Characterization of the Molecular Fragment That Is Responsible for Agonism of Pergolide at Serotonin 5-Hydroxytryptamine2B and 5-Hydroxytryptamine2A Receptors

“…35 S]GTP␥S assay as previously described (Schlotter et al, 2005) using membranes of CHO cells stably expressing hD 2L and hD 2S receptors (Hayes et al, 1992). Homogenates of membranes were prepared according to the literature (Hü bner et al, 2000) with receptor densities of B max ϭ 1.11 and 1.44 pmol/g for D 2L and D 2S , respectively, diluted in HEPES buffer (20 mM HEPES, 10 mM MgCl 2 , 100 mM NaCl, pH 7.4), and incubated at 37°C with 1 M GDP (HEPES buffer) and the test compound (in HEPES buffer supplemented with 0.1 mM dithiothreitol) applying eight different concentrations (0.01-100,000 nM) as hexaduplicates at a final volume of 200 l in 96-well microplates. After 30 min, 0.1 nM […”