TY - JOUR
T1 - Synthesis and Evaluation of 6,7-Dihydroxy-2,3,4,8,9,13b-hexahydro-1H-benzo[6,7]cyclohepta[1,2,3-ef][3]benzazepine, 6,7-Dihydroxy-1,2,3,4,8,12b-hexahydroanthr[10,4a,4-cd]azepine, and 10-(Aminomethyl)-9,10-dihydro-1,2-dihydroxyanthracene as Conformationally Restricted Analogs of β-Phenyldopamine
AU - Snyder, Scott E.
AU - Aviles-Garay, Felix A.
AU - Chakraborti, Ratna
AU - Nichols, David E.
AU - Watts, Val J.
AU - Mailman, Richard B.
PY - 1995/6/1
Y1 - 1995/6/1
N2 - The present study was designed to define the geometry of the hydrophobic accessory region for binding of dopamine D1 receptor ligands and to assess the relative importance of ethylamine side chain conformation for receptor affinity. Three compounds, 6,7-dihydroxy-2,3,4,8,9,13b-hexahydro-1H-benzo[6,7]cyclohepta[1,2,3-ef][3]benzazepine, 4, 6,7-dihydroxy-1,2,3,4,8,12b-hexahydroanthr[10,4a,4-cd]azepine, 5, and 10-(aminomethyl)-9,10-dihydro-1,2-dihydroxyanthracene, 6, were synthesized as conformationally restricted analogs of β-phenyldopamine. Molecular modeling studies were performed to compare these three compounds with the high-affinity D1 agonists dihydrexidine (DHX), 2, and SKF 38393, 3. The β-phenyl moieties in the target compounds are constrained by means of either an ethyl (4) or methylene (5 and 6) bridge. The compounds adopt minimum-energy conformations in which the β-phenyl group is approximately -22° (4), -12° (5), and -30° (6) from coplanarity with the catechol ring. These compounds also embody either a freely rotating (6) or a rigidified gauche (4 and 5) rotameric conformation of the dopamine ethylamine side chain, the latter nearly perfectly superimposible on the benzazepine portion of SKF 38393. Radioligand competition experiments showed that compounds 4,5, and 6 have only micromolar affinity for both the D1 and D2 dopamine receptor subtypes. The low affinity of 4-6, relative to 2 and 3, may be due to improper orientation of the β-phenyl moiety and provides important information about the three-dimensional orientation of the hydrophobic accessory binding domain of the dopamine D1 receptor. In addition, the negligible affinity of 6, as compared to 2 and 3, indicates that the rotameric positioning of the ethylamine side chain may not be a primary determinant of receptor affinity.
AB - The present study was designed to define the geometry of the hydrophobic accessory region for binding of dopamine D1 receptor ligands and to assess the relative importance of ethylamine side chain conformation for receptor affinity. Three compounds, 6,7-dihydroxy-2,3,4,8,9,13b-hexahydro-1H-benzo[6,7]cyclohepta[1,2,3-ef][3]benzazepine, 4, 6,7-dihydroxy-1,2,3,4,8,12b-hexahydroanthr[10,4a,4-cd]azepine, 5, and 10-(aminomethyl)-9,10-dihydro-1,2-dihydroxyanthracene, 6, were synthesized as conformationally restricted analogs of β-phenyldopamine. Molecular modeling studies were performed to compare these three compounds with the high-affinity D1 agonists dihydrexidine (DHX), 2, and SKF 38393, 3. The β-phenyl moieties in the target compounds are constrained by means of either an ethyl (4) or methylene (5 and 6) bridge. The compounds adopt minimum-energy conformations in which the β-phenyl group is approximately -22° (4), -12° (5), and -30° (6) from coplanarity with the catechol ring. These compounds also embody either a freely rotating (6) or a rigidified gauche (4 and 5) rotameric conformation of the dopamine ethylamine side chain, the latter nearly perfectly superimposible on the benzazepine portion of SKF 38393. Radioligand competition experiments showed that compounds 4,5, and 6 have only micromolar affinity for both the D1 and D2 dopamine receptor subtypes. The low affinity of 4-6, relative to 2 and 3, may be due to improper orientation of the β-phenyl moiety and provides important information about the three-dimensional orientation of the hydrophobic accessory binding domain of the dopamine D1 receptor. In addition, the negligible affinity of 6, as compared to 2 and 3, indicates that the rotameric positioning of the ethylamine side chain may not be a primary determinant of receptor affinity.
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U2 - 10.1021/jm00013a015
DO - 10.1021/jm00013a015
M3 - Article
C2 - 7608904
AN - SCOPUS:0029040856
SN - 0022-2623
VL - 38
SP - 2395
EP - 2409
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 13
ER -