Multifunctional ligands of opioid and SSRIs (43-54) have been designed by using rational and in Silico methodologies. Opioid and SSRIs multivalent ligands (43-54) were synthesized by functionalizing escitalopram (6) entity and fentanyl (17) like structure and keeping intact the rest of the structural features of opioid and SSRIs pharmacophores. Multifunctional ligands have been synthesized by direct combination (53-54) or adding
some spacers or linkers (43-52) into them by solution phase peptide strategy for the cure of pain and depression in a single molecule concurrently. The synthesized ligands (43-54) were characterized by spectroscopic analysis i.e.,1H NMR, 13C NMR, LRMS, HRMS. Multitarget screening of multifunctional ligands (43-54) was carried out on different brain receptors. Primary binding assay of opioid and SSRIs multifunctional ligands (43-54) have been checked for their opioids (μ, δ and κ receptors) and SSRIs multifunctional activities. Most of the ligands like (45 Ki μ =0.7 nM, δ = 0.91 nM, κ =9 nM), (53 Ki μ
=0.8 nM, δ = 0.1 nM and κ = 0.9 nM) and (54 Ki μ =1.2 nM, δ = 0.8 nM and κ =0.3 nM) showed high binding affinity values for μ, δ and κ-opioid receptors and low values for SSRIs receptors. Functional assays of multifunctional ligands (42-43) have been carried out. Further outcomes showed that these ligands (43-54) are best analgesics than multifunctional activities and could be designed in future as lead of a class of antidepressants i.e., triple re-uptake inhibitors (TRIs) whose mechanism of action is
almost same as that of opioid.