In-vitro investigation of oxazol and urea analogues of morphinan at opioid receptors

Abstract

A series of 2-amino-oxazole (7 & 8) analogs and 2-one-oxazole analogs (9 &10) were synthesized from cyclorphan (1) or butorphan (2) and evaluated in-vitro by their binding affinity at μ, δ and κ opioid receptors and compared with their 2-aminothiozole analogs 5 & 6. Ligands 7-10 showed decreased affinities at κ and μ receptors.Urea analogues (11-14) were also prepared from 2-aminocyclorphan (3) or 2-aminobutorphan (4) and evaluated in-vitro by their binding affinity at μ, δ and κ opioid receptors. The urea derived opioids retained their affinities at μ receptors while showing increased affinities at δ receptors and decreased affinities at κ receptors. Functional activities of these compounds were measured in the [ 35 S] GTPγS binding assay, illustrating that all of these ligands were κ agonists. At the μ receptor, compounds 11 and 12 were μ agonist/antagonists.

Synthesis, Binding Affinity, and Functional in Vitro Activity of 3-Benzylaminomorphinan and 3-Benzylaminomorphine Ligands at Opioid Receptors

“…2-Nitro-3-hydroxy -N -cyclopropylmethylmorphinan 13 9 (2.4 g, 6.7 mmol) was dissolved in anhydrous dichloromethane (50 mL) and Et 3 N (3.2 mL, 19.3 mmol). The mixture was cooled to 0°C, and then Tf 2 O (1.8 mL, 9.6 mmol) was added.…”

“…TBDPS was routinely removed with TBAF to yield the desired ligands ( 11a – c ), which after O-demethylation gave 12a – c . For the preparation of 2-amino-3-desoxymorphinan ( 16 ), cyclorphan was first nitrated with HNO 3 /HCOOH to afford 13 and then triflated to yield 2-nitromorphinan-3-triflate ( 14 ). The triflate was reduced to 2-nitro-3-desoxymorphinan ( 15 ) using Pd(OAc) 2 /dppp/Et 3 SiH .…”

“…The organic layer was filtered and concentrated under reduced pressure, and the crude product was purified on silica gel (EtOAc/Et 3 N, 200:1) to give the title product 8 as a white foam (2.94 g, 93%). 1 H NMR (300 MHz, CDCl 3 ) δ 7.82 (dd, J = 7.4, 1.6 Hz, 2H), 7.68 (dd, J = 7.6, 1.3 Hz, 2H), 7.53−7.31 (m, 6H), 6.93 J = 8.4 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 5.74 (d, J = 9.7 Hz, 1H), 5.18 (dt, J = 9.7, 2.6 Hz, 1H), 4.51 (d, J = 5.0 Hz, 1H), 4.18 (dd, J = 5.2, 2.7 Hz, 1H), 3.28 (dd, J = 5.9, 3.0 Hz, 1H), 3.03 (d, J = 19.1 Hz, 1H), 2.52−2.21 (m, 4H), 2.37 (s, 3H), 1.85−1.63 (m, 2H), 1.12 (s, 9H); 13 3-Amino-6-(tert-butyldiphenylsilyl)oxymorphine (9). Under nitrogen atmosphere, morphine-6-(tert-butyldiphenylsilyl)oxy-3-(trifluoromethanesulfonate) (8) (2.93 g, 4.47 mmol) was dissolved in anhydrous THF (50 mL), and Pd(OAc) 2 (50 mg, 0.224 mmol), rac-BINAP (279 mg, 0.448 mmol), and benzophenone imine (1.05 g, 5.81 mmol) were added to the stirring solution.…”

“…Pale yellow solid (125 mg, 30%); 1 H NMR (300 MHz, CD 3 OD) δ 7.20 (t, J = 7.8 Hz, 1H), 7.07 (dd, J = 8.2, 2.9 Hz, 1H), 6.95−6.76 (m, 4H), 5.79 (d, J = 9.9 Hz, 1H), 5.39 (d, J = 10.0 Hz, 1H), 5.19 (d, J = 6.2 Hz, 1H), 4.49 (m, 3H), 4.45 (s, 1H), 4.27 (s, 1H), 3.48−2.87 (m, 7H), 3.01 (s, 3H), 2.53 (t, J = 11.5 Hz, 1H), 2.14 (d, J = 13.9 Hz, 1H), 1.42−1.25 (m, 1H), 0.07 (d, J = 15.3 Hz, 1H); 13 2-Nitro-3-trifluoromethylsulfonyloxy-N-cyclopropylmethylmorphinan (14). 2-Nitro-3-hydroxy-N-cyclopropylmethylmorphinan 13 9 (2.4 g, 6.7 mmol) was dissolved in anhydrous dichloromethane (50 mL) and Et 3 N (3.2 mL, 19.3 mmol). The mixture was cooled to 0 °C, and then Tf 2 O (1.8 mL, 9.6 mmol) was added.…”

“…6 Schiller and coworkers 7 reported that replacement of the Tyr residue in TIPP peptides with a Bcp or Dbcp residue resulted in a general increase in DOR binding affinity. We have reported the modification of the phenolic hydroxyl group of cyclorphan and butorphan, such as carbamate, 8 oxazole, 9 urea, 9 and aminothiazole 10 analogues, which maintain high binding affinity. In continuing these studies on the development of effective analgesics and/or treatment for opioid addiction, we focused our interests on the structural modification and pharmacological evaluation of analogs of cyclorphan and butorphan, especially in the development of new MOR selective ligands.…”