Bifunctional ligands (151-162) of opioid and SSRIs have been designed such as, rationally and in Silico by functionalization of two pharmacophores keeping intact the structural features of opioid and SSRIs such as, escitalopram and fentanyl like moieties, by direct combination and by introducing some spacers into them using solution phase peptide strategy for the treatment of pain and depression in a single molecule simultaneously to avoid the side effects. The synthesized ligands (151-162) were characterized by spectroscopic analysis such as, 1H NMR, 13C NMR, LRMS, HRMS. Multitarget screening of bifunctional ligands (151-162) of various brain receptors have been carried out. Primary binding assay of opioid and SSRIs bifunctional ligands (151-162) have been tested for their μ, δ and κ-opioid and SSRIs bifunctional activities. Most of the compounds 151 (Ki μ = 0.5 nM, δ = 0.5 nM and κ = 0.9 nM) and 152 (Ki μ = 0.3 nM, δ = 0.7 nM and κ = 1.1 nM) showed high affinities for μ δ and κ-opioid receptors
and low affinities for SSRIs receptors. Functional assays of bifunctional ligands (151-162) have been performed. Further results proved that these ligands (151-162) are excellent analgesics than bifunctional ligands and correspondingly could be designed in future as triple re-uptake inhibitors (TRIs) a class of antidepressants.