Design, Synthesis, and Evaluation of Metabolism-Based Analogues of Haloperidol Incapable of Forming MPP+-like Species

Abstract

The long-term, irreversible, Parkinsonism-like side effects of haloperidol have been speculated to involve several mechanisms. More recently, it has been speculated that the metabolic transformation to MPP+-like species may contribute to the Parkinsonism-like side effects. Because BCPP+ and its reduced analogue have been shown to possess the potential to destroy dopamine receptors in the nigrostriatum, we have designed new analogues of haloperidol lacking the structural features necessary to form neurotoxic quaternary species but retaining their dopamine-binding capacity. The most potent agent at the D2 receptor, the homopiperidine analogue 11, was found to be equipotent to haloperidol. It was also of interest to identify analogues with DA binding profiles similar to that of clozapine at the dopamine receptor subtypes. Evaluation of the proposed agents shows that the ratio of D2 to D4 (2) binding of clozapine was mimicked by 7 [K(i)(D2) = 33, K(i)(D3) = 200, K(i)(D4) = 11 nM; K(i)(D2)/K(i)(D4) = 3] and 9 [K(i)(D2) = 44, K(i)(D3) = 170, K(i)(D4) = 24 nM; K(i)(D2)/K(i)(D4) = 2]. A preliminary in-vivo testing of compound 7 shows that its behavioral profile is similar to that of clozapine. This profile suggests that there is a need for further evaluation of these two synthetic agents and their enantiomers for efficacy and lack of catalepsy in animal models.

Sila‐Haloperidol, a Silicon Analogue of the Dopamine (D2) Receptor Antagonist Haloperidol: Synthesis, Pharmacological Properties, and Metabolic Fate

“…[2] The unfortunate short-and irreversible long-term extrapyramidal side effects (EPSs), including Parkinsonism-like tardive dyskinesia, present a drawback, particularly in lengthy therapies with haloperidol (1 a), and have motivated the search for haloperidol analogues and other "atypical" antipsychotics that exhibit fewer EPSs. [3] With these considerations in mind, we examined the biological effects of sila-substitution (C/Si exchange) [4] of haloperidol (1 a) and thus synthesized its silicon analogue, sila-haloperidol (1 b), [5] whereby the R 3 COH carbon atom in the piperidine ring was replaced by a silicon atom. In context with our systematic research on silicon-based drugs, [6] we carried out a full characterization of 1 b·HCl (solution NMR studies, crystal structure analysis, ESI-MS studies of aqueous solutions) complemented by radioligand binding studies on hD 1 , hD 2 , hD 4 , and hD 5 human dopamine receptors at that time.…”

“…In addition, we also present the missing pharmacological data for the hD 3 receptor, and we reinvestigated the affinities of 1 a and 1 b for all the other human dopamine receptors. As the antipsychotic effect of haloperidol (1 a) is supported by its interaction with s receptors, [8] and selective s receptor antagonists are considered "atypical" antipsychotics, [9] the s 1 and s 2 receptor affinities of the C/Si analogues 1 a and 1 b were also studied.…”

“…Because inhibition of CYP450 enzymes is responsible for many severe side effects of drugs, the IC 50 values of 1 a and 1 b for the five major CYP isoforms were measured as well. As one of the metabolites of haloperidol (1 a) has been speculated to be responsible for the longterm, irreversible Parkinsonism-like side effects of this drug, [3] we were also interested in the metabolic fate of sila-haloperidol (1 b) and performed comparative in vitro studies of the metabolism of the C/Si analogues 1 a and 1 b using human liver microsomes. This broad spectrum of studies aimed at a representative assessment of the potential of the carbon/silicon switch strategy [4,6] for drug design.…”

Analogues of the dopamine D2 receptor antagonist L741,626: Binding, function, and SAR

“…Retention of the C-4 piperidine sp3 carbon was previously reported to be preferred by the D2 receptor 12 and replacement of the 4-piperidinol function with other groups was explored (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). In general, none of these analogues showed higher affinity for D2 than the parent compound.…”

Stetter Reaction in Room Temperature Ionic Liquids and Application to the Synthesis of Haloperidol

“…[17] The 1,4-adduct of p-fluorobenzaldehyde and methyl acrylate 7, prepared as described previously, was used as the starting material for a short synthesis of haloperidol (Scheme 3). After protection of the carbonyl as a ketal group affording 11, the ester was reduced to the aldehyde 12 in good yield using DIBAL-H at low temperature.…”