Multi-targeted drug design strategies for the treatment of schizophrenia

ABSTRACT

Introduction

Schizophrenia is a complex psychiatric disease (or a conglomeration of disorders) manifesting with positive, negative and cognitive symptoms. The pathophysiology of schizophrenia is not completely known; however, it involves many neurotransmitters and their receptors. In order to treat schizophrenia, drugs need to be multi-target drugs. Indeed, the action of second and third generation antipsychotics involves interactions with many receptors, belonging mainly to aminergic GPCRs.

Areas covered

In this review, the authors summarize current concepts of schizophrenia with the emphasis on the modern dopaminergic, serotoninergic, and glutamatergic hypotheses. Next, they discuss treatments of the disease, stressing multi-target antipsychotics. They cover different aspects of design of multi-target ligands, including the application of molecular modeling approaches for the design and benefits and limitations of multifunctional compounds. Finally, they present successful case studies of multi-target drug design against schizophrenia.

Expert opinion

Treatment of schizophrenia requires the application of multi-target drugs. While designing single target drugs is relatively easy, designing multifunctional compounds is a challenge due to the necessity to balance the affinity to many targets, while avoiding promiscuity and the problems with drug-likeness. Multi-target drugs bring many benefits: better efficiency, fewer adverse effects, and drug–drug interactions and better patient compliance to drug regime.

KEYWORDS:

• Antipsychotics
• multi-target drugs
• polypharmacology
• schizophrenia

Article highlights

• Schizophrenia is a disease of a complex pathomechanism and its treatment requires multi-target drugs.

• Second generation multi-target antipsychotics are currently used to treat schizophrenia.

• Experimental and computational approaches complement each other to search for drugs with polypharmacological profile.

• In comparison to combination treatments, multi-target drugs exhibit a number of benefits: more predictable pharmacokinetics, fewer drug–drug interactions and better patient compliance.

• Current efforts to develop compounds to treat schizophrenia focus on multi-target compounds affecting aminergic GPCRs combined in some cases with SSRI pharmacophores.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One referee declares that they serve as a consultant for Novus Medical Education and on the advisory board for Pharmacy Times Health-System Edition. They have also received honoraria from the American Journal of Managed Care, the American Physician Institute, Pharmacy Times, PlatformQ Health and Specialty Pharma Education Center. They also serve on the speaker’s bureau for Otsuka Pharmaceuticals. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript was funded by an OPUS grant from the National Science Center (NCN, Poland), grant number 2017/27/B/NZ7/01767 (to AA Kaczor).