Conjugated enynes as nonaromatic catechol bioisosteres: synthesis, binding experiments, and computational studies of novel dopamine receptor agonists recognizing preferentially the D(3) subtype.
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.
Hübner
H
H
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.
Haubmann
C
C
Utz
W
W
Gmeiner
P
P
D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D003514:Cyclohexylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018491:Dopamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011437:Propylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014297:Trimethylsilyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C405049:(4-ethynylcyclohex-3-enyl)dipropylamine; D000480:Alkynes; D003514:Cyclohexylamines; D018491:Dopamine Agonists; D011437:Propylamines; D017448:Receptors, Dopamine D2; D014297:Trimethylsilyl Compounds; C405048:dipropyl(4-trimethylsilylethynylcyclohex-3-enyl)amine