Chimeric Structures in Mental Illnesses-"Magic" Molecules Specified for Complex Disorders

Abstract

Mental health problems cover a wide spectrum of diseases, including mild to moderate anxiety, depression, alcohol/drug use disorders, as well as bipolar disorder and schizophrenia. Pharmacological treatment seems to be one of the most effective opportunities to recover function efficiently and satisfactorily. However, such disorders are complex as several target points are involved. This results in a necessity to combine different types of drugs to obtain the necessary therapeutic goals. There is a need to develop safer and more effective drugs. Considering that mental illnesses share multifactorial processes, the paradigm of one treatment with multiple modes of action rather than single-target strategies would be more effective for successful therapies. Therefore, hybrid molecules that combine two pharmacophores in one entity show promise, as they possess the desired therapeutic index with a small off-target risk. This review aims to provide information on chimeric structures designed for mental disorder therapy (i.e., schizophrenia and depression), and new types of drug candidates currently being tested. In addition, a discussion on some benefits and limitations of multifunctional, bivalent drug candidates is also given.

Keywords: chimeric compounds; depression; efficacy; mental disorders; schizophrenia.

Figure 1

Types of multitarget therapies.

Figure 2

Comparison of multitarget compounds vs. hybrid compounds with multitarget properties. Multitarget compounds that are not bivalent hybrid molecules do not possess specific building fragments corresponding to original drugs or other known ligands. On the other hand, they are characterized by having recognized and privileged small fragments/regions that are able to target different systems (e.g., heterocyclic cores, aliphatic residues). In contrast, hybrid compounds encompass one or more bioactive compounds from a different class or their pharmacophoric subunits (drug A, drug B) into one molecule, thereby representing the desired features of the original drugs. In the figure, the hybrid structure is built on the basis of a conjugation of pharmacophores connected via any cleavable linker (e.g., esters, amides, carbamates, or disulfide bonds).

Figure 3

Classification of hybrid ligands (chimeras) based on pharmacophore (P) linking.

Figure 4

Mode of hybrid drugs related to target interactions.

Figure 5

Structures of designed hybrid compounds with anti-schizophrenic properties. (A–E) Series of conjugates containing the biphenyl pharmacophore and arylpiperazine-like pharmacophore; (F) sumanirole–aripiprazole hybrid; (G) ziprasidone; (H) clozapine–docosahexaenoic acid; (I) DCG-IV; (J,K) GABA-based conjugates (AN168 and AN187, respectively).

Figure 6

Structures of designed antidepressant hybrids: JZ-IV-10 (lower structure) and 7n (upper structure).