Structure–activity relationship studies of SYA 013, a homopiperazine analog of haloperidol

Bioorganic & Medicinal Chemistry

Etukala

et al. 2016

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5-HT1A and 5-HT7 receptors have been at the center of discussions recently due in part to their major role in the etiology of major central nervous system diseases such as depression, sleep disorders, and schizophrenia. As part of our search to identify dual targeting ligands for these receptors, we have carried out a systematic modification of a selective 5HT7 receptor ligand culminating in the identification of several dual 5-HT1A and 5-HT7 receptor ligands. Compound 16, a butyrophenone derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low nanomolar binding affinities to both receptors. Interestingly, compound 16 also displayed moderate affinity to other clinically relevant dopamine receptors. Thus, it is anticipated that compound 16 may serve as a lead for further exploitation in our quest to identify new ligands with the potential to treat diseases of CNS origin.

Section: Chemistrymentioning

confidence: 99%

“…Sulfoxide 9 was prepared by oxidation of 8 using the previously reported meta peroxybenzoic acid ( m -CPBA) mediated oxidative conditions depicted in Scheme 5. 23 …”

Section: Chemistrymentioning

confidence: 99%

Design and synthesis of dual 5-HT1A and 5-HT7 receptor ligands

Ofori

Bioorganic & Medicinal Chemistry

Etukala

et al. 2016

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“…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.…”

mentioning

confidence: 99%

Further evaluation of the tropane analogs of haloperidol

Sampson

Bricker

Bioorganic & Medicinal Chemistry Letters

et al. 2014

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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.

“…The commercially available 4-chloro-1-(4-fluorophenyl)-butan-1-one ( 29 ) was converted to 4-chloro-1-(4-fluorophenyl)-2-methylenebutan-1-one ( 30 ) by refluxing in acetic anhydride in the presence of hexamethylenetriamine. 10,13 Compound 30 was cyclized by heating in concentrated sulfuric acid to produce 2-(2-chloroethyl)-5-fluoro-2,3-dihydro-1H-inden-1-one ( 31 ) which was protected by reaction with ethylene glycol to form the 1,3-dioxolane, 32 . Alkylating 4-(4-chlorophenyl)piperazine with 32 and deprotecting the dioxolane resulted in the formation of the desired target compound 8 (Scheme 1).…”

Section: Chemistrymentioning

confidence: 99%

“…10–12 A frequent observation in such studies was the fact that unlike the piperidine analogs of haloperidol, the piperazine analogs demonstrated selective and significant affinities to the D 4 receptor subtype. Chart 1 displays common D 4 selective ligands with the piperazine pharmacophore.…”

Section: Introductionmentioning

confidence: 99%

Identification of a new selective dopamine D4 receptor ligand

Sampson

Bioorganic & Medicinal Chemistry

Eyunni

et al. 2014

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The dopamine D4 receptor has been shown to play key roles in certain CNS pathologies including addiction to cigarette smoking. Thus, selective D4 ligands may be useful in treating some of these conditions. Previous studies in our laboratory have indicated that the piperazine analog of haloperidol exhibits selective and increased affinity to the DAD4 receptor subtype, in comparison to its piperidine analog. This led to further exploration of the piperazine moiety to identify new agents that are selective at the D4 receptor. Compound 27 (KiD4 = 0.84 nM) was the most potent of the compounds tested. However, it only had moderate selectivity for the D4 receptor. Compound 28 (KiD4 = 3.9 nM) while not as potent, was more discriminatory for the D4 receptor subtype. In fact, compound 28 has little or no binding affinity to any of the other four DA receptor subtypes. In addition, of the 23 CNS receptors evaluated, only two, 5HT1AR and 5HT2BR, have binding affinity constants better than 100 nM (Ki < 100 nM). Compound 28 is a potentially useful D4-selective ligand for probing disease treatments involving the D4 receptor, such as assisting smoking cessation, reversing cognitive deficits in schizophrenia and treating erectile dysfunction. Thus, further optimization, functional characterization and evaluation in animal models may be warranted.