Optimization of the Activity Profile and Wider Selectivity

FIGURE 27.13 Mu-opioid-plus DMLs for treating pain. 

CHAPTER 27 Multi-target Drugs Strategies and Challenges for Medicinal Chemists 

A difference in the in vitro activities may sometimes be desirable where a different level of receptor occupancy for each target is associated with a desired pharmacological effect. The atypical profile of the anti-psychotic drug, clozapine, has been variously associated with its lower activity at the D4 or 5-HT2a receptors compared to the 

D2 receptor. Neuroimaging studies have shown that an optimal D2 receptor occupancy of 60-70% is sufficient to produce an atypical anti-psychotic effect, and if D2 receptor occupancy is too high, the atypical profile can be lost even in the presence of high 5-HT2 occupancy. Several atypical anti-psychotics with low D2/5-HT2 binding ratios have now been introduced onto the market such as ziprasidone 11. 

FIGURE 27.14 Optimization of a DML profile to enhance efficacy and safety. 

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