R-1484

Haloperidol is a typical antipsychotic drug (APD) associated with an increased risk of extrapyramidal side effects (EPSs) and hyperprolactinemia relative to atypical APDs such as clozapine. Both drugs are dopamine D₂ receptor (D₂R) antagonists, with contrasting kinetic profiles. Haloperidol displays fast association/slow dissociation at the D₂R, whereas clozapine exhibits relatively slow association/fast dissociation. Recently, we have provided evidence that slow dissociation from the D₂R predicts hyperprolactinemia, whereas fast association predicts EPS. Unfortunately, clozapine can cause severe side effects independent of its D₂R action. Our results suggest an optimal kinetic profile for D₂R antagonist APDs that avoids EPS. To begin exploring this hypothesis, we conducted a structure-kinetic relationship study of haloperidol and revealed that subtle structural modifications dramatically change binding kinetic rate constants, affording compounds with a clozapine-like kinetic profile. Thus, optimization of these kinetic parameters may allow development of novel APDs based on the haloperidol scaffold with improved side-effect profiles.

In general, 4-RC₆H₄CO(CH₂)₃N.CH₂.CH₂.C(OH)-(4-R'C₆H₄).CH₂.CH₂ (I) were prepared by condensation in PhMe of Bz(CH₂)₃Cl (II) or 4-FC₆H₄CO(CH₂)₃Cl (III) with 4-R'C₆H₄C(OH).CH₂.CH₂.NH.CH₂.CH₂ (IV).Cl(CH₂)₃CO-Cl (71 g.) in 70 ml. C₆H₆ underwent the Friedel-Craft reaction in the usual way with C₆H₆ (or PhF) to yield 80% II, b₅ 134-7°, n²⁰_D 1.541 (or 80-95% III, b₆ 136-42°, n²⁰_D 1.523.IV were prepd, in 8 steps from α-methylstyrene (V) and its derivatives V (944 g.) added slowly at 60° to 856 g. NH₄Cl in 3 1.1.36% H₂CO, stirred until the temperature fell to 40°, 2 1. MeOH added, the mixture stirred 20 hrs., MeOH removed in vacuo, the residue in 3 1. concentrated HCl heated at 100°, cooled, diluted with 2 1. H₂O, made alk. with 15N NaOH, and extracted with C₆H₆ yielded 46-50% 4-R'C₆H₄C:CH.CH₂.NH.CH₂.CH₂ (VI) (R' = H), b₁ 97-112°, n²⁵_D 1.586, HCl salt m. 199-202°, λ 248 mμ (ε 11,700).Other VI were similarly prepared from derivatives of V [R', b.p., λ (mμ) (ε) given]: F, 139-41°/4, 245.5 (10,100); Cl, 167-70°/8, 254.6 (14,100); Me, 162-70°/10, 251 (11,300).Dry HBr gas passed 7 hrs. at 10-20 through a stirred solution of 160 g. VI in 500 ml. AcOH, the mixture kept 16 hrs. at room temperature, AcOH and excess HBr removed in vacuo at 40°, and the residue taken up in ether and filtered yielded the HBr salt (VII) of 4-R'C₆H₄CBr.CH₂.CH₂.NH.CH₂.CH₂ (R', m.p. given): H, 209.5-10.5°; F, 143-4°; Cl, 213-15°; Me, 190-2°.VII (160 g.) in 3 1. H₂O was hydrolyzed with 20% NaOH to IV [R', m.p., λ (mμ) (ε) given]: H, 159-60°, 260 (225); F, 116.4-17.6°, 266 (815); Cl, 134.4-6.0°, 269.5 (460); Me, 136-7°, 265.5 (295).II (8.7 g.) (or III) heated at 100-10° in a closed tube with 14.2 g. IV (R = R' = H), 0.1 g. KI, and 150 ml. PhMe, the cooled reaction mixture filtered from the separated solid, and the filtrate concentrated yielded 70% I, m. 129.4-30.6°, λ 246 mμ (ε 12,600), HCl salt m. 182-4°.Other I were similarly prepared [R, R', m.p., λ (mμ) (ε), m.p. of HCl salt given]: H, F, 117.4-18.6°, 245 (13,300), 188-90°; H, Cl, 128.2-30.2°, 245.5 (13,400), 216.5-18.0°; H, Me, 101-2.5°, 245 (13,000), 179.6-81.5°; F, H, 135.6-6.2°, 246.5 (12,500), 204.5-5.5.°; F, F, 120-1°, 247 (12,400), 201-3.5°; F, Cl, 148-9.4°, 247 (11,900), 226-7.5°; and F, Me, 118-19.5° 246.5 (12,200), 212-13°.Some pharmacol. properties in mice of these 8 compounds of structure I were determined and compared with those of 20 known CNS depressants.All possessed potent CNS depressant effects in low doses.Some relations between structure and potency were suggested.