Design, Synthesis, and Biological Evaluation of the Third Generation 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl)carboxamido]morphinan (NAP) Derivatives as μ/κ Opioid Receptor Dual Selective Ligands

Abstract

μ opioid receptor (MOR) agonists have been widely applied for treating moderate to severe pain. However, numerous adverse effects have been associated with their application, including opioid-induced constipation (OIC), respiratory depression, and addiction. On the basis of previous work in our laboratory, NAP, a 6β-N-4′-pyridyl substituted naltrexamine derivative, was identified as a peripheral MOR antagonist that may be used to treat OIC. To further explore its structure–activity relationship, a new series of NAP derivatives were designed, synthesized, and biologically evaluated. Among these derivatives, NFP and NYP significantly antagonized the antinociception effect of morphine. Whereas NAP acted mainly peripherally, its derivatives NFP and NYP actually can act centrally. Furthermore, NFP produced significantly lesser withdrawal symptoms than naloxone at similar doses. These results suggest that NFP has the potential to be a lead compound to treat opioid abuse and addiction.

Synthesis, Structure, and Biological Activity of Novel Bispidine Derivatives

“…Hot solutions of 0.9 g (0.0033 mol) of 3-cyclopropanmethyl-7-(3isopropoxypropyl)-3,7-diazabicyclo[3.3.1]nonane (5) in 25 ml of ethyl alcohol and 3.7 g (0.0033 mol) of β-cyclodextrin in 35 ml of distilled water were mixed together. The mixture was placed in a drying cupboard, ethanol and water were evaporated at 50-55°C to produce 4.5 g of compound (11).…”

“…The interest of chemists in the study of heteroanalogs of bicyclo [3.3.1] nonane is due to the unique properties of these compounds, which makes them valuable from a theoretical and practical point of view [1][2][3][4][5][6][7][8][9][10]. It is also known that methylenecyclopropane residue is a valuable structural unit of bioactive compounds, particularly, opiate antagonists [11,12]. 1-(3-Isopropoxypropyl-and 3-ethoxypropyl-)-4-oxopiperidine (1,2) as starting substrates was used to obtain the target bispidines (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) according to Fig.…”

“…It is also known that methylenecyclopropane residue is a valuable structural unit of bioactive compounds, particularly, opiate antagonists [11,12]. 1-(3-Isopropoxypropyl-and 3-ethoxypropyl-)-4-oxopiperidine (1,2) as starting substrates was used to obtain the target bispidines (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) according to Fig. 1.…”

“…To study the biological properties of the novel derivatives of 3,7-diazabicyclo[3.3.1]nonan-9-ones, their complexes with β-cyclodextrin had been synthesized (11)(12)(13)(14).…”

Computational Methods for Understanding the Selectivity and Signal Transduction Mechanism of Aminomethyl Tetrahydronaphthalene to Opioid Receptors

“…Additionally, opioid antagonists such as naloxone and naltrexone were used to treat opioid abuse, which did not have the side effects related to the MOR agonism. Some scientists make many efforts to develop newly selective MOR antagonists or μ/κ opioid receptor dual ligands for the treatment of opioid use disorder ( Figure 2 ) [ 17 , 18 , 19 ], and NFP could produce significantly fewer withdrawal symptoms than naloxone at similar doses in vivo.…”