Multi-receptor drug design: Haloperidol as a scaffold for the design and synthesis of atypical antipsychotic agents

Abstract

Using haloperidol as a scaffold, new agents were designed to investigate the structural contributions of various groups to binding at CNS receptors associated with atypical antipsychotic pharmacology. It is clear that each pharmacophoric group, the butyrophenone, the piperidine and the 4-chlorophenyl moieties contributes to changes in binding to the receptors of interest. This strategy has resulted in the identification of several new agents, compounds 16, 18, 19, 23, 24 and 25, with binding profiles which satisfy our stated criteria for agents to act as potential atypical antipsychotics. This research demonstrates that haloperidol can serve as a useful lead in the identification and design of new agents that target multiple receptors associated with antipsychotic pharmacology.

Further evaluation of the tropane analogs of haloperidol

“…It was also observed that replacement of the carbonyl functional group in haloperidol with an oxygen or a sulfur atom retains D 2 binding and increases affinity at the 5-HT 1A receptor, indicating that the carbonyl group is not essential for binding at the D 2 R but can be replaced with other groups to produce compounds that bind with high affinity to the receptors associated with antipsychotic properties. 8 …”

“…8–10 The alkylating agent, (3-chloropropyl)(4-fluorophenyl)sulfane, was prepared using the procedure in our previously published paper, 8 with slight modification, by refluxing 4-fluorobenzenethiol and 1-bromo-3-chloropropane in the presence of K 2 CO 3 in iPrOH. The other two alkylating agents were similarly prepared by using the corresponding n-fluorobenzenethiol.…”

“…Having been aware that replacement of the fluorine atom on the butyrophenone moiety with other substituents resulted in significant changes in binding affinities, 8 we synthesized the other two fluorinated analogs with the fluorine atom located at the meta ( 9 ) and the ortho ( 10 ) positions on the butyrophenone moiety. The analogs were subsequently screened and the results are recorded in Table 1.…”

Development of CNS multi-receptor ligands: Modification of known D2 pharmacophores

“…2, 21, 22 In this article, we explored different modifications to pharmacophoric groups (Figure 1) present in ligands that have high affinity for CNS receptors or elaborated structurally similar functionalities to such pharmacophores. The working hypothesis was that by modifying the arylalkyl groups attached to the amino groups in the pharmacophores shown in Figure 1, it was possible to broaden the affinity of a target compound to other CNS receptors including the D 2 R, 5-HT 1A R, 5-HT 7 R and SERT.…”

Novel small molecule guanidine Sigma1 inhibitors for advanced prostate cancer

“…Using the commercially available bis-boc-pyrazolocarboxamidine (AstaTech, Inc.; CAS No. : 862686-58-6) we synthesized the alcohol side chain, 23 and then installed it via a Mitsunobu reaction 27 to provide the di- N -boc pyrazole guanidine reagent (Scheme 4; R = H) as a suitable advanced intermediate envisioned for the synthesis of numerous analogs derived from anilines.…”