PMC

Structures of the classic histamine H₁ antagonist, the stereoisomeric pairs are indicated with ‘*’ on the structures.

Summary of SAR of the BZT analogues at the DAT and histamine H₁ receptors, with effect of substitution on increase ([unk]) and decrease ([unk]) in activities.

Superimposition of compounds 16 (capped stick; colored by atom type) and 19 (capped stick; colored by atom type) on cyproheptadine (ball and stick; Yellow) with receptor essential volume for the histamine H₁ receptor in blue contours at the C-2 and C-6 positions of the tropane ring.

Linear regression of histamine H₁ receptor affinities and DAT affinities among BZT analogues. The r² value of the linear regression was 0.0020, which was not significant (P=0.7587). The inset in the figure shows the distribution of the points when low affinity outliers are excluded.

Definition of the receptor interaction points (dummy atoms). The atoms for superimposition A (c1, c2, N), B (a1, b1, a2, b2, N), C (c1, c2, d1) and D (a1, b1, a2, b2, d1) were used. The pharmacophoric distances DI (c1-N), DII (c2-N) and DIII (c1-c2) with angle between the planes of the aromatic rings were measured.

(a), A difference in volume of N-8 substituted BZT analogues 14 (magenta) and 15 (yellow) from the template cyproheptadine (green) is shown as a blue contour. (b) A plot of the ΔVs with the activity of BZT analogues (N=10) at the histamine H₁ receptor, excluded compounds (◆) are shown in the graph.

Left: Superimposition of histamine H₁-antagonists (“cis” and “trans” rings are shown on left and right side of the molecules), with receptor excluded volume (orange surface). The cyproheptadine (ball and stick; colored by atom type), carbinoxamine S (capped stick, Red) and carbinoxamine R (capped stick; green) are shown. Right: Superimposition of the BZT analogues on histamine H₁ pharmacophore. Receptor excluded region for the DAT (cyan) and H₁-receptor (blue) with cyproheptadine (ball and stick, colored by atom type) and Compound 2 (capped stick, magenta) are depicted. The receptor essential volume, green and yellow contours are shown for compounds 9 (capped stick; red) and 4 (capped stick; blue) respectively.