Conformational Analysis and Molecular Modeling of 1-Phenyl-, 4-Phenyl-, and l-Benzyl-l,2,3,4-tetrahydroisoquinolines as D1Dopamine Receptor Ligands

Paul S. Charifson, J. Phillip Bowen, Steven D. Wyrick, Andrew J. Hoffman, Michael Cory, Andrew T. McPhail, Richard Mailman

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


Conformational studies on a series of 1-phenyl-, 4-phenyl-, and l-benzyl-l,2,3,4-tetrahydroisoquinolines that possess an identical substituent pattern to the prototypical D1dopamine receptor antagonist SCH23390 [(R)-(+)-7-chloro-8-hydroxy-3-methyl-l-phenyl-2,3,4,5-tetrahydro-lif-3-benzazepine (1)] were performed with use of molecular mechanics calculations {MM2(85), with newly developed aromatic halide bending and torsional parameters that are now incorporated into MM2(87)}, single-crystal X-ray analysis, and high-field NMR spectroscopy. The synthesis and biological testing of compounds 2–7 has been previously reported. The test compounds were compared both quantitatively and graphically to compound 1. Calculations on both the free-base and protonated forms of each compound were carried out. To insure that conformation space was adequately sampled, the test compounds were energy minimized from different starting geometries; ring inversion of the heterocycle was employed, as were dihedral driver calculations on the phenyl or benzyl rings. For N-methyl-6-chloro-7-hydroxy-l-phenyl-l,2,3,4-tetrahydroisoquinoline (2), it was determined that the torsion angle r(C8a-Cl-Cl2-Cl7) had energy minima at approximately 60° and 240°. This finding was corroborated by NMR studies that indicated a dramatic upfield chemical shift of ArH8 after ring cyclization. The nitrogen lone pair or hydrogen vector was approximately orthogonal to the plane of the substituted aromatic ring in the tetrahydroisoquinolines; this explained the upfield chemical shift of the vicinal chiral proton (H1). In all instances, the 6-membered heterocyclic ring in the energy-minimized structures preferred the half-chair conformation with the phenyl rings pseudo-equatorial. Distance comparisons of the proposed pharmacophoric atoms (Cl, N, 0, centroid of the phenyl or benzyl ring) showed that the phenyl or benzyl centroid to ammonium H distance, Cl to N distance, and distance of the nitrogen above or below the plane of the isoquinoline aromatic ring are the distances most highly correlated with biological activity (r = 0.82, 0.75, 0.81, respectively). Resolution and single-crystal X-ray analysis of compound 2 showed the most active enantiomer to possess the S absolute configuration, in contrast to the benzazepine (R)-l. Least-squares fitting of the energy-minimized structures with SYBYL molecular modeling software showed (S)-(+)-2, rather than (R)-(-)-2, gave a better fit to (R)-1. Volume determinations derived from sybyl multifit analyses aided in receptor mapping to qualitatively describe areas of “active” pharmacophore space as well as areas of “inactive” substituent space. A correlation (r = 0.95) was found relating the calculated dipole moment orientations with D1receptor binding affinity.

Original languageEnglish (US)
Pages (from-to)2050-2058
Number of pages9
JournalJournal of Medicinal Chemistry
Issue number9
StatePublished - Sep 1 1989

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery


Dive into the research topics of 'Conformational Analysis and Molecular Modeling of 1-Phenyl-, 4-Phenyl-, and l-Benzyl-l,2,3,4-tetrahydroisoquinolines as D1Dopamine Receptor Ligands'. Together they form a unique fingerprint.

Cite this