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

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

Benzothiazoles as probes for the 5HT1A receptor and the serotonin transporter (SERT): A search for new dual-acting agents as potential antidepressants

The synthesis and evaluation of several benzothiazole based compounds are described in an attempt to identify novel dual-acting 5HT1A receptor and SERT inhibitors as new antidepressants. Binding affinities at the 5HT1A receptor and the serotonin transporter do not appear to be congruent and other areas of the binding sites would need to be explored in order to improve binding simultaneously at both sites. Compounds 20 and 23 show moderate binding affinity at the 5HT1A receptor and the SERT site and thus, have the potential to be further explored as dual-acting agents. In addition, compound 20 binds with low affinity to the dopamine transporter (DAT), the norepinephrine transporter (NET) and 5HT2C receptor, which are desirable properties as selectivity for SERT (and not DAT or NET) is associated with an absence of cardiovascular side-effects

Synthesis and evaluation of ligands for D2-like receptors: The role of common pharmacophoric groups

Arylcycloalkylamines, such as phenyl piperidines and piperazines and their arylalkyl substituents, constitute pharmacophoric groups exemplified in several antipsychotic agents. A review of previous reports indicates that arylalkyl substituents can improve the potency and selectivity of the binding affinity at D2-like receptors. In this paper, we explored the contributions of two key pharmacophoric groups, i.e., 4′-fluorobutyrophenones and 3-methyl-7-azaindole groups, to the potency and selectivity of synthesized agents at D2-like receptors. Preliminary observation of binding affinities indicates that there is little predictability of specific effects of the arylalkyl moieties but the composite structure is responsible for selectivity and potency at these receptors

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

Structure–activity relationship studies on 4-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-1-(4-fluorophenyl) butan-1-one (SYA 013), a homopiperazine analog of haloperidol has resulted in an understanding of the effect of structural modifications on binding affinity at dopamine and serotonin receptor subtypes. Further exploration, using bioisosteric replacement strategies has led to the identification of several new agents including compounds 7, 8, 11 and 12 which satisfy the initial criteria for further exploration as new antipsychotic agents. In addition, compound 18, a D3 selective tropanol, has been identified as having the potential for further optimization into a useful drug which may combat neuropsychiatric diseases

Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-Chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one

The synthesis and exploration of novel butyrophenones have led to the identification of a diazepane analog of haloperidol, 4-[4-(4-Chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (Compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, 5HT subtype receptors, H-1, M-1 receptors and at NET, DAT and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED50 value

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

5-HT and 5-HT 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 5HT receptor ligand culminating in the identification of several dual 5-HT and 5-HT receptor ligands. Compound , a butyrophenone derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low nanomolar binding affinities to both receptors. Interestingly, compound also displayed moderate affinity to other clinically relevant dopamine receptors. Thus, it is anticipated that compound may serve as a lead for further exploitation in our quest to identify new ligands with the potential to treat diseases of CNS origin

Further evaluation of the tropane analogs of haloperidol

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

Identification of a new selective dopamine D4 receptor ligand

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