In these review series, recent reports on the design and development of analgesic molecules were reviewed. The primary aim is to examine heterocyclic frameworks involved in pain modulation and, where applicable, to establish structure - activity relationships (SARs). Currently, nine major pathways have been described for pain relief, including prostaglandin synthesis inhibition, opioid receptor modulation, sodium channel blockade, enhancement of serotonin and norepinephrine levels, cannabinoid receptor (CBR) binding, N-methyl-D-aspartate (NMDA) receptor antagonism, transient receptor potential cation channel subfamily V member 1 (TRPV1) antagonism, and P2X purinergic receptor blockade. After reviewing literature, owing to extensive research in this field, the study was divided into two separate parts, azoles and non-azoles. In this first study, the molecules exhibiting analgesic activity containing azole-based rings such as pyrrole, pyrazole, indole, imidazole, benzimidazole, indazole, triazole, tetrazole, (benz)oxazole, thiazole, benzothiazole, oxadiazole, and thiadiazole were comprehensively reviewed. These ring systems were classified in the whole study, first according to their molecular weights and then by bioisosteric similarity. Accordingly, this review also provides a framework for the compounds incorporating these core structures in the design of novel molecules with potential analgesic properties. In conclusion, these works highlight the current progress and emerging strategies in analgesic drug discovery and development.
Keywords: Analgesic activity; SAR; aliphatic heterocycles; aromatic heterocycles; azoles; drug design.
Analgesia is a common symptom associated with tissue damage, infection, and various chronic diseases such as diabetes and cancer. The primary cause should be treated in order to relieve the pain. In recent years, numerous biological pathways involved in analgesia have been identified, and many analgesic drugs are now available on the market. In these review series (Heterocyclics I and Heterocyclics II), recent analgesic compounds are classified based on their chemical structures and mechanisms of action. SARs are discussed where sufficient and meaningful data are available, particularly concerning the ring systems. The drug design and development processes, as well as the identified research gaps and potential advantages in the existing literature, are comprehensively evaluated for all relevant ring systems. Additionally, novel formulation strategies for marketed drugs are examined. The findings suggest that drug design and development in the field of analgesia are highly dynamic, with frequent updates and innovations. While the ring system(s) present in a molecule are important, it is fundamentally the three-dimensional features, such as bond angles and binding orientations or modes, that determine the mechanism of action.