Haloperidol: towards further understanding of the structural contributions of its pharmacophoric elements at D2-like receptors

Sikazwe, Donald; Li, Shouming; Mardenborough, Leroy G.; Cody, Vivian; Roth, B. L.; Ablordeppey, Seth Y.

doi:10.1016/j.bmcl.2004.09.046

Cited by 21 publications

(30 citation statements)

References 8 publications

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“…2a and 2b) of L741,626 that show D2 selectivity over D3 and D4 receptors have been reported. 11,12 In this report, 2b demonstrated a >100-fold D3/D2 selectivity that appeared to be related to the addition of a 5-OCH 3 onto the indolyl moiety of 2a. This study and many others describing D3-selective ligands demonstrate the importance and potential differences in pendant aryl ring substitution that may provide separation between D2 and D3 receptor recognition.…”

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confidence: 54%

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

Grundt¹,

Husband²,

Luedtke³

et al. 2007

Bioorganic & Medicinal Chemistry Letters

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A series of analogues of the dopamine D2 receptor antagonist L741,626 were synthesized and evaluated for binding and function at D2 family receptor subtypes. Several analogues showed comparable binding profiles to the parent ligand, however, in general, chemical modification served to reduce D2 binding affinity and selectivity. Keywords Dopamine D2 receptor antagonistsThe neurotransmitter dopamine has been associated with fine movement coordination, cognition, emotion, affect, memory, and the regulation of prolactin secretion by the pituitary reward system. 1 Alterations in dopaminergic function are not only involved in the pathogenesis of Parkinson's disease 2 and schizophrenia, 3 but also occur as a consequence of acute and chronic abuse of pyschostimulants. 4 Therefore, the D1-like (D1 and D5) and the D2-like (D2, D3, and D4) dopamine receptor families have been targets for the development of treatment medications for these disorders. 5-8The majority of antipsychotic medications are nonselective dopamine D2 receptor antagonists that frequently produce undesirable extrapyramidal side effects upon chronic exposure. As such, to date the discovery of highly selective dopamine D2 antagonists has been elusive in part because the therapeutic value of such agents has been perceived as minimal due to the association of this receptor exclusively with the unwanted side effects of nonselective D2 receptor antagonists. Furthermore the high degree of amino acid homology within the binding sites of the D2-like receptors provides a formidable challenge to discovering highly selective and potent D2 (or D3) antagonists. 7, 9 Nevertheless, the discovery of D2 receptor selective antagonists and partial agonists would provide important pharmacological tools to determine the role of the D2-like receptor subtypes in 1) the mechanism of action of antipsychotic agents, 2) the etiology of drug-induced extrapyramidal side effects, and 3) the contribution of the D2 * Corresponding author. Tel.: +1-410-550-6568; fax: +1-410-550-6855; e-mail address: anewman@intra.nida.nih.gov Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errorsmaybe discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. and D3 receptor subtypes in the CNS reward system. In addition, such D2 receptor selective compounds would also be a starting point for the development of radioligands. NIH Public AccessA decade ago, a D2-selective antagonist, L741,626 (1) was reported amongst a series of D4-selective agents to bind with ∼40-fold higher affinity to D2 over D3 receptors and is currently being used as a D2-selective antagonist in animal models of drug abuse. 10 During the course of our inves...

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confidence: 54%

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

Grundt¹,

Husband²,

Luedtke³

et al. 2007

Bioorganic & Medicinal Chemistry Letters

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“…1,5,4 Modifications of the piperidine ring resulting in D 2 receptor binding profiles that are similar or better than haloperidol and which could not form toxic pyridinium metabolites, were also identified. 4,6,7 These studies have indicated that adding an ethylene bridge to the piperidine moiety to form a tropane analog, maintained or increased affinity for the D 2 receptor subtype. 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.…”

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confidence: 99%

Further evaluation of the tropane analogs of haloperidol

Sampson

Bricker

Xiao-lin

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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Previous work from our labs has indicated that a tropane analog of haloperidol with potent D2 binding but designed to avoid the formation of MPP+-like metabolites, such as 4-(4-chlorophenyl)-1-(4-(4-fluorophenyl)-4-oxobutyl)pyridin-1-ium (BCPP+) still produced catalepsy, suggesting a strong role for the D2 receptor in the production of catalepsy in rats, and hence EPS in humans. This study tested the hypothesis that further modifications of the tropane analog to produce compounds with less potent binding to the D2 receptor than haloperidol, would produce less catalepsy. These tests have now revealed that while haloperidol produced maximum catalepsy, these compounds produced moderate to low levels of catalepsy. Compound 9, with the least binding affinity to the D2R, produced the least catalepsy and highest Minimum Adverse Effective Dose (MAED) of the analogs tested regardless of their affinities at other receptors including the 5-HT1AR. These observations support the hypothesis that moderation of the D2 binding of the tropane analogs could reduce catalepsy potential in rats and consequently EPS in man.

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“…29–31 The flunarizine pharmacophore ( 4 ) was also included for evaluation as flunarizine has been shown to demonstrate multiple CNS actions. 39 We have hypothesized that by attaching various aryl alkyl groups to these pharmacophores, it is possible to obtain compounds which can bind to the D 2 R and other clinically relevant receptors including 5-HT 1A R and 5-HT 7 R. In particular, it was of interest to attach aryl (benzothiazole-, benzoxazole- and indole-) alkyl groups in view of their observed effects on binding affinity to CNS receptors.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously shown that these pharmacophores can be manipulated to control their CNS receptor binding profiles. 29–31 Using the previously synthesized benzothiazole- or benzoxazole- linked alkyl groups, 4-chlorophenyl piperidinol was targeted for alkylation to produce compounds 18–20 (Schemes 1–3). These compounds were synthesized and screened at the same receptors as before and the results are reported in Table 3.…”

Section: Resultsmentioning

confidence: 99%

“…Pharmacophore 6 was previously synthesized. 29–31 To synthesize the target compounds 7–22 , different alkylating agents were required as depicted in Figure 2. Alkylating groups 28–29 were obtained by reacting 5-chloropentanoyl chloride or 4-chlorobutanoyl chloride with 2-aminobenzenethiol as previously reported, 21, 32 while 30 was synthesized from 2-amino-4-chlorobenzenethiol and 5-chloropentanoyl chloride using the same procedure.…”

Section: Chemistrymentioning

confidence: 99%

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

Etukala

Xiao-lin

Eyunni

et al. 2016

Bioorganic & Medicinal Chemistry

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Several known D2 pharmacophores have been explored as templates for identifying ligands with multiple binding affinities at dopamine and serotonin receptors considered as clinically relevant receptors in the treatment of neuropsychiatric diseases. This approach has resulted in the identification of ligands that target multiple CNS receptors while avoiding others associated with deleterious effects. In particular, compounds 11, 15 and 22 may have potential for further development as antipsychotic agents as they favorably interact with the clinically relevant receptors including D2R, 5-HT1AR, and 5-HT7R. We have also identified the pair of compounds 11 and 10 as high affinity D2R ligands with and without SERT binding affinities, respectively. These differential binding profiles endow the pair with the potential for evaluating SERT contributions to antipsychotic drug activity in animal behavioral models. In addition, compound 11 has no significant affinity for 5-HT2CR and binds only moderately to the H1R, suggesting it may not induce weight gain or sedation when used clinically. Taken together, compound 11 displays an interesting pharmacological profile that necessitates the evaluation of its functional and in vivo effects in animal models which are currently ongoing.

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Haloperidol: towards further understanding of the structural contributions of its pharmacophoric elements at D2-like receptors

Cited by 21 publications

References 8 publications

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

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

Further evaluation of the tropane analogs of haloperidol

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

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