HPLC (gradient A): retention time = 37.5. at MOR and exhibited an increased DOR binding affinity when compared to the unsubstituted parent compounds 4a and 15a, presumably due to the carbonyl moiety incorporated into each of the = 0.9, 1H), 7.39 (br s, 1H), 7.35 (dd, = 8.2, 2.2, 1H), 7.29 (t, = 7.4, 2H), 7.23C7.16 (m, 3H), 4.20 (t, = 6.2, 2H), 3.98 (s, 2H), 2.75 (t, = 6.2, 2H), 2.58 (q, = 7.4, 2H), 1.20 (t, = 7.4, 3H). 13C NMR (126 MHz, CDCl3) 194.27, 173.03, 142.21, 140.13, 138.78, 134.63, 128.90, 128.71, 127.62, 126.49, 126.11, 124.44, 43.88, 41.29, 39.62, 27.98, 9.91. 6-Benzyl-1-butyryl-2,3-dihydroquinolin-4(1= 1.3, 1H), 7.39C7.34 (m, 2H), 7.33C7.25 (m, 2H), 7.25C7.16 (m, 3H), 4.21 (t, = 6.2, 2H), 3.99 (s, 2H), 2.76 (t, = 6.2, 2H), 2.54 (t, = 8.0, 2H), 1.79C1.66 (m, 2H), 0.95 (t, = 7.4, 3H). 13C NMR (101 MHz, CDCl3) 194.37, 172.35, 142.31, 140.18, 138.87, 134.71, 128.99, 128.80, 127.77, 126.58, 126.18, 124.55, 43.97, 41.38, 39.82, 36.57, 19.25, 13.94. 6-Benzyl-1-isobutyryl-2,3-dihydroquinolin-4(1= 2.0 Hz, 1H), 7.37C7.25 (m, 4H), 7.25C7.17 (m, 3H), 4.21 (t, = 6.3 Hz, 2H), 3.99 (s, 2H), 3.14 (hept, = 6.7 Hz, 1H), 2.75 (t, = 6.2 Hz, 2H), 1.18 (d, = 6.7 Hz, 6H). 13C NMR (126 MHz, CDCl3) 194.33, 176.97, 142.29, 140.05, 138.84, 134.59, 128.90, 128.87, 128.68, 127.64, 126.46, 126.15, 124.22, 43.90, 41.25, 39.79, 31.13, 19.88. 6-Benzyl-1-(cyclopropanecarbonyl)-2,3-dihydroquinolin-4(1= 2.2, 1H), 7.46 (d, = 8.3, 1H), 7.35 (dd, = 8.4, 2.2, 1H), 7.31C7.26 (m, 2H), 7.22C7.17 (m, 3H), 4.26 (t, = 6.3, 2H), 3.98 (s, 2H), 2.76 (t, = 6.3, 2H), 2.06C1.96 (m, 1H), 1.21C1.15 (m, 2H), 0.91C0.82 (m, 2H). 13C NMR (126 MHz, CDCl3) 194.41, 173.00, 142.45, 140.13, 138.53, 134.49, 128.89, 128.71, 127.74, 126.49, 125.85, 124.09, 43.53, 41.28, 39.70, 13.74, 9.77. 6-Benzyl-1-(cyclobutanecarbonyl)-2,3-dihydroquinolin-4(1= 1.3, 1H), 7.48C7.37 (br s, 1H), 7.35 (dd, = 8.2, 2.2, 1H), 7.29 (t, = 7.5, 2H), 7.24C7.13 (m, 3H), 4.12 (t, = 6.2, 2H), 3.98 (s, 2H), 3.52 (p, = 8.4, 1H), 2.72 (t, = 6.2, 2H), 2.43 (dq, = 11.8, 9.2, 2H), 2.13 (q, = 9.9, 2H), 2.02C1.88 (m, 2H). 13C NMR (126 MHz, CDCl3) 194.09, 174.02, 142.14, 140.14, 138.52, 134.63, 128.85, 128.64, 127.49, 126.41, 125.75, 123.84, 43.78, 41.24, 39.57, 37.95, 25.72, 17.83. Methyl 6-Benzyl-4-oxo-3,4-dihydroquinoline-1(2= 2.1 Hz, 1H), 7.71 (d, = 8.6 Hz, 1H), 7.34 (dd, = 8.6, 2.2 Hz, 1H), 7.29 (t, = 7.5 Hz, 2H), 7.23C7.16 (m, 3H), 4.18 (t, = 6.3 Hz, 2H), 3.97 (s, 2H), 3.84 (s, 3H), 2.76 (t, = 6.3 Hz, 2H). 13C NMR (126 MHz, CDCl3) 193.79, 154.23, 141.74, 140.24, 137.32, 134.79, 128.74, 128.51, 127.13, 126.25, 124.79, 123.58, 53.30, 44.40, 41.09, 38.81. 6-Benzyl-1-(2-methoxyacetyl)-2,3-dihydroquinolin-4(1= 2.2 Hz, 1H), 7.37 (dd, = 8.4, 2.2 Hz, 1H), 7.28 (t, = 7.6 Hz, 2H), 7.23C7.15 (m, 3H), 4.26 (s, 2H), 4.17 (t, = 6.3 Hz, 2H), 3.98 (s, 2H), 3.45 (s, 3H), 2.78 (t, = 6.2 Hz, 2H). 13C NMR (126 MHz, CDCl3) 193.62, 168.07, 141.25, 139.91, 139.02, 134.72, 128.77, 128.58, 128.55, 127.56, 126.37, 125.78, 123.66, 76.74, 71.84, 59.24, 43.95, 41.17, 39.41. 1-Benzoyl-6-benzyl-2,3-dihydroquinolin-4(1= 2.1 Hz, 1H), 7.42C7.34 (m, 3H), 7.31C7.25 (m, 2H), 7.22C7.17 (m, 2H), 7.14C7.10 (m, 1H), 7.08C7.04 (m, 2H), 7.01 (dd, = 8.5, 2.2 Hz, 1H), 6.81 (d, = 8.4 Hz, 1H), 4.21 (t, = 6.3 Hz, 2H), 3.85 (s, 2H), 2.77 (t, = 6.3.13C NMR (126 MHz, CDCl3) 153.43, 140.77, 136.51, 136.42, 128.88, 128.71, 128.55, 128.47, 128.34, 125.97, 123.89, 80.97, 55.52, 50.36, 41.08, 40.00, 29.41, 28.22, 22.48. (= 8.3, 2.1, 1H), 4.53 (t, = 4.6, 1H), 3.95 (s, 2H), 3.94C3.85 (m, 1H), 3.80C3.68 (m, 1H), 3.34 (br s, 1H), 2.51C2.41 (m, 2H), 2.27C2.15 (m, 1H), 2.08C1.97 (m, 1H), 1.74C1.63 (m, 2H), 1.20 (s, 9H), 0.92 (t, = 7.4, 3H). (= 8.2, 2.2 Hz, 1H), 4.53 (q, = 3.9 Hz, 1H), 3.96 (s, 2H), 3.94C3.89 (m, 1H), 3.75C3.67 (m, 1H), 3.30 (bs, 1H), 3.12 (p, = 6.9 Hz, 1H), 2.24C2.15 (m, 1H), 2.08C1.98 (m, 1H), 1.23C1.16 (s, 9H), 1.13 (dd, = 9.0, 6.7 Hz, 6H). as average SEM. ****, < 0.0001 for 4a and 4h for the 10 mg/kg dose when compared to baseline, < 0.001 for 4f when compared to baseline (not indicated on graph). (B) Time course of antinociception of 4a and 4h (= 3) in the mouse WWTW assay following ip administration of 10 mg/kg. Plotted as average SEM. Data for 4a from ref (8). Discussion and Conclusions All new analogues across both series sets, excluding 4m, maintained high binding affinity at MOR and exhibited an increased DOR binding affinity when compared to the unsubstituted parent compounds 4a and 15a, presumably due to the carbonyl moiety incorporated into each of the = 0.9, 1H), 7.39 (br s, 1H), 7.35 (dd, = 8.2, 2.2, 1H), 7.29 (t, = 7.4, 2H), 7.23C7.16 (m, 3H), 4.20 (t, = 6.2, 2H), 3.98 (s, 2H), 2.75 (t, = 6.2, 2H), 2.58 (q, = 7.4, 2H), 1.20 (t, = 7.4, 3H). 13C NMR (126 MHz, CDCl3) 194.27, 173.03, 142.21, 140.13, 138.78, 134.63, 128.90, 128.71, 127.62, 126.49, 126.11, 124.44, 43.88, 41.29, 39.62, 27.98, 9.91. 6-Benzyl-1-butyryl-2,3-dihydroquinolin-4(1= 1.3, 1H), 7.39C7.34 (m, 2H), 7.33C7.25 (m, 2H), 7.25C7.16 (m, 3H), 4.21 (t, = 6.2, 2H), 3.99 (s, 2H), 2.76 (t, = 6.2, 2H), 2.54 (t, = 8.0, 2H), 1.79C1.66 (m, 2H), 0.95 (t, = 7.4, 3H). 13C NMR (101 MHz, CDCl3) 194.37, 172.35, 142.31, 140.18, 138.87, 134.71, 128.99, 128.80, 127.77, 126.58, 126.18, 124.55, 43.97, 41.38, 39.82, 36.57, 19.25, 13.94. 6-Benzyl-1-isobutyryl-2,3-dihydroquinolin-4(1= 2.0 Hz, 1H), 7.37C7.25 (m, 4H), 7.25C7.17 (m, 3H), 4.21 (t, = 6.3 Hz, 2H), 3.99 (s, 2H), 3.14 (hept, = 6.7 Hz, 1H), 2.75 (t, = 6.2 Hz, 2H), 1.18 (d, = 6.7 Hz, 6H). 13C NMR (126 MHz, CDCl3) 194.33, 176.97, 142.29, 140.05, 138.84, 134.59, 128.90, 128.87, 128.68, 127.64, 126.46, 126.15, 124.22, 43.90, 41.25, 39.79, 31.13, 19.88. 6-Benzyl-1-(cyclopropanecarbonyl)-2,3-dihydroquinolin-4(1= 2.2, 1H), 7.46 (d, = 8.3, 1H), 7.35 (dd, = 8.4, 2.2, 1H), 7.31C7.26 (m, 2H), 7.22C7.17 (m, 3H), 4.26 (t, = 6.3, 2H), 3.98 (s, 2H), 2.76 (t, = 6.3, 2H), 2.06C1.96 (m, 1H), 1.21C1.15 (m, 2H), 0.91C0.82 (m, 2H). 13C NMR (126 MHz, CDCl3) 194.41, 173.00, 142.45, 140.13, 138.53, 134.49, 128.89, 128.71, 127.74, 126.49, 125.85, 124.09, 43.53, 41.28, 39.70, 13.74, 9.77. 6-Benzyl-1-(cyclobutanecarbonyl)-2,3-dihydroquinolin-4(1= 1.3, 1H), 7.48C7.37 (br s, 1H), 7.35 (dd, = 8.2, 2.2, 1H), 7.29 (t, = 7.5, 2H), 7.24C7.13 (m, 3H), 4.12 (t, = 6.2, 2H), 3.98 (s, 2H), 3.52 (p, = 8.4, 1H), 2.72 (t, = 6.2, 2H), 2.43 (dq, = 11.8, 9.2, 2H), 2.13 (q, = 9.9, 2H), 2.02C1.88 (m, 2H). 13C NMR (126 MHz, CDCl3) 194.09, 174.02, 142.14, 140.14, 138.52, 134.63, 128.85, 128.64, 127.49, 126.41, 125.75, 123.84, 43.78, 41.24, 39.57, 37.95, 25.72, 17.83. Methyl 6-Benzyl-4-oxo-3,4-dihydroquinoline-1(2= 2.1 Hz, 1H), 7.71 (d, = 8.6 Hz, 1H), 7.34 (dd, = 8.6, 2.2 Hz, 1H), 7.29 (t, = 7.5 Hz, 2H), 7.23C7.16 (m, 3H), 4.18 (t, = 6.3 Hz, 2H), 3.97 (s, 2H), 3.84 (s, 3H), 2.76 (t, = 6.3 Hz, 2H). 13C NMR (126 MHz, CDCl3) 193.79, 154.23, 141.74, 140.24, 137.32, 134.79, 128.74, 128.51, 127.13, 126.25, 124.79, 123.58, 53.30, 44.40, 41.09, 38.81. 6-Benzyl-1-(2-methoxyacetyl)-2,3-dihydroquinolin-4(1= 2.2 Hz, 1H), 7.37 (dd, = 8.4, 2.2 Hz, 1H), 7.28 (t, = 7.6 Hz, 2H), 7.23C7.15 (m, 3H), 4.26 (s, 2H), 4.17 (t, = 6.3 Hz, 2H), 3.98 (s, 2H), 3.45 (s, 3H), 2.78 (t, = 6.2 Hz, 2H). 13C NMR (126 MHz, CDCl3) 193.62, 168.07, 141.25, 139.91, 139.02, 134.72, 128.77, 128.58, 128.55, 127.56, 126.37, 125.78, 123.66, 76.74, 71.84, 59.24, 43.95, 41.17, 39.41. 1-Benzoyl-6-benzyl-2,3-dihydroquinolin-4(1= 2.1 Hz, 1H), 7.42C7.34 (m, 3H), 7.31C7.25 (m, 2H), 7.22C7.17 (m, 2H), 7.14C7.10 (m, 1H), 7.08C7.04 (m, 2H), 7.01 (dd, = 8.5, 2.2 Hz, 1H), 6.81 (d, = 8.4 Hz, 1H), 4.21 (t, = 6.3 Hz, 2H), 3.85 (s, 2H), 2.77 (t, = 6.3 Hz, 2H). 13C NMR (126 MHz, CDCl3) 193.73, 170.04, 142.60, 139.99, 138.06, 135.06, 134.31, 130.99, 128.78, 128.58, 128.47, 128.39, 127.38, 126.36, 124.82, 124.63, 45.30, 41.10, 39.50. (= 8.2 Hz, 1H), 7.29C7.21 (m, 2H), 7.20C7.15 (qd, = 6.5, 5.4, 1.6 Hz, 4H), 7.06 (dd, = 8.5, 2.3 Hz, 1H), 4.52 (q, = 3.4 Hz, 1H), 3.97C3.87 (m, 3H), 3.57 (tdd, = 12.9, 4.2, 1.7 Hz, 1H), 3.32 (bs, 1H), 2.20C2.13 (m, 1H), 1.99C1.90 (m, 1H), 1.50 (s, 9H), 1.19 (s, 9H). 13C NMR (126 MHz, CDCl3) 153.43, 140.77, 136.51, 136.42, 128.88, 128.71, 128.55, 128.47, 128.34, 125.97, 123.89, 80.97, 55.52, 50.36, 41.08, 40.00, 29.41, 28.22, 22.48. (= 8.3, 2.1, 1H), 4.53 (t, = 4.6, 1H), 3.95 (s, 2H), 3.94C3.85 (m, 1H), 3.80C3.68 (m, 1H), 3.34 (br s, 1H), 2.51C2.41 (m, 2H), 2.27C2.15 (m, 1H), 2.08C1.97 (m, 1H), 1.74C1.63 (m, 2H), 1.20 (s, 9H), 0.92 (t, = 7.4, 3H). (= 8.2, 2.2 Hz, 1H), 4.53 (q, = 3.9 Hz, 1H), 3.96 (s, 2H), 3.94C3.89 (m, 1H), 3.75C3.67 (m, 1H),.The recently obtained crystal structure of mouse MOR in the active conformation (PDB ID: 5c1m)30 was used as a template for homology modeling of active conformations of DOR and KOR. (= 3) in the mouse WWTW assay following ip administration of 10 mg/kg. Plotted as average SEM. Data for 4a from ref (8). Discussion and Conclusions All new analogues across both series sets, excluding 4m, maintained high binding affinity at MOR and exhibited an increased DOR binding affinity when compared to the unsubstituted parent compounds 4a and 15a, presumably due to the carbonyl moiety incorporated into each of the = 0.9, 1H), 7.39 (br s, 1H), 7.35 (dd, = 8.2, 2.2, 1H), 7.29 (t, = 7.4, 2H), 7.23C7.16 (m, 3H), 4.20 (t, = 6.2, 2H), 3.98 (s, 2H), 2.75 (t, = 6.2, 2H), 2.58 (q, = 7.4, 2H), 1.20 (t, = 7.4, 3H). 13C NMR (126 MHz, CDCl3) 194.27, 173.03, 142.21, 140.13, 138.78, 134.63, 128.90, 128.71, 127.62, 126.49, 126.11, 124.44, 43.88, 41.29, 39.62, 27.98, 9.91. 6-Benzyl-1-butyryl-2,3-dihydroquinolin-4(1= 1.3, 1H), 7.39C7.34 (m, 2H), 7.33C7.25 (m, 2H), 7.25C7.16 (m, 3H), 4.21 (t, = 6.2, 2H), 3.99 (s, 2H), 2.76 (t, = 6.2, 2H), 2.54 (t, = 8.0, 2H), 1.79C1.66 (m, 2H), 0.95 (t, = 7.4, 3H). 13C NMR (101 MHz, CDCl3) 194.37, 172.35, 142.31, 140.18, 138.87, 134.71, 128.99, 128.80, 127.77, 126.58, 126.18, 124.55, 43.97, 41.38, 39.82, 36.57, 19.25, 13.94. 6-Benzyl-1-isobutyryl-2,3-dihydroquinolin-4(1= 2.0 Hz, 1H), 7.37C7.25 (m, 4H), 7.25C7.17 (m, 3H), 4.21 (t, = 6.3 Hz, 2H), 3.99 (s, 2H), 3.14 (hept, = 6.7 Hz, 1H), 2.75 (t, = 6.2 Hz, 2H), 1.18 (d, = 6.7 Hz, 6H). 13C NMR (126 MHz, CDCl3) 194.33, 176.97, 142.29, 140.05, 138.84, 134.59, 128.90, 128.87, 128.68, 127.64, 126.46, 126.15, 124.22, 43.90, 41.25, 39.79, 31.13, 19.88. 6-Benzyl-1-(cyclopropanecarbonyl)-2,3-dihydroquinolin-4(1= 2.2, 1H), 7.46 (d, = 8.3, 1H), 7.35 (dd, = 8.4, 2.2, 1H), 7.31C7.26 (m, 2H), 7.22C7.17 (m, 3H), 4.26 (t, = 6.3, 2H), 3.98 (s, 2H), 2.76 (t, = 6.3, 2H), 2.06C1.96 (m, 1H), 1.21C1.15 (m, 2H), 0.91C0.82 (m, 2H). 13C NMR (126 MHz, CDCl3) 194.41, 173.00, 142.45, 140.13, 138.53, 134.49, 128.89, 128.71, 127.74, 126.49, 125.85, 124.09, 43.53, 41.28, 39.70, 13.74, 9.77. 6-Benzyl-1-(cyclobutanecarbonyl)-2,3-dihydroquinolin-4(1= 1.3, 1H), 7.48C7.37 (br s, 1H), 7.35 (dd, = 8.2, 2.2, 1H), 7.29 (t, = 7.5, 2H), 7.24C7.13 (m, 3H), 4.12 (t, = 6.2, 2H), 3.98 (s, 2H), 3.52 (p, = 8.4, 1H), 2.72 (t, = 6.2, 2H), 2.43 (dq, = 11.8, 9.2, 2H), 2.13 (q, = 9.9, 2H), 2.02C1.88 (m, 2H). 13C NMR (126 MHz, CDCl3) 194.09, 174.02, 142.14, 140.14, 138.52, 134.63, 128.85, 128.64, 127.49, 126.41, 125.75, 123.84, 43.78, 41.24, 39.57, 37.95, 25.72, 17.83. Methyl 6-Benzyl-4-oxo-3,4-dihydroquinoline-1(2= 2.1 Hz, 1H), 7.71 (d, = 8.6 Hz, 1H), 7.34 (dd, = 8.6, 2.2 Hz, 1H), 7.29 (t, = 7.5 Hz, 2H), 7.23C7.16 (m, 3H), 4.18 (t, = 6.3 Hz, 2H), 3.97 (s, 2H), 3.84 (s, 3H), 2.76 (t, = 6.3 Hz, 2H). 13C NMR (126 MHz, CDCl3) 193.79, 154.23, 141.74, 140.24, 137.32, 134.79, 128.74, 128.51, 127.13, 126.25, 124.79, 123.58, 53.30, 44.40, 41.09, 38.81. 6-Benzyl-1-(2-methoxyacetyl)-2,3-dihydroquinolin-4(1= 2.2 Hz, 1H), 7.37 (dd, = 8.4, 2.2 Hz, 1H), 7.28 (t, = 7.6 Hz, 2H), 7.23C7.15 (m, 3H), 4.26 (s, 2H), Zatebradine hydrochloride 4.17 (t, = 6.3 Hz, 2H), 3.98 (s, 2H), 3.45 (s, 3H), 2.78 (t, = 6.2 Hz, 2H). 13C NMR (126 MHz, CDCl3) 193.62, 168.07, 141.25, 139.91, 139.02, 134.72, 128.77, 128.58, 128.55, 127.56, 126.37, 125.78, 123.66, 76.74, 71.84, 59.24, 43.95, 41.17, 39.41. 1-Benzoyl-6-benzyl-2,3-dihydroquinolin-4(1= 2.1 Hz, 1H), 7.42C7.34 (m, 3H), 7.31C7.25 (m, 2H), 7.22C7.17 (m, 2H), 7.14C7.10 (m, 1H), 7.08C7.04 (m, 2H), 7.01 (dd, = 8.5, 2.2 Hz, 1H), 6.81 (d, = 8.4 Hz, 1H), 4.21 (t, = 6.3 Hz, 2H), 3.85 (s, 2H), 2.77 (t, = 6.3 Hz, 2H). 13C NMR (126 MHz, CDCl3) 193.73, 170.04, 142.60, 139.99, 138.06, 135.06, 134.31, 130.99, 128.78, 128.58, 128.47, 128.39, 127.38, 126.36, 124.82, 124.63, 45.30, 41.10, 39.50. (= 8.2 Hz, 1H), 7.29C7.21 (m, 2H), 7.20C7.15 (qd, = 6.5, 5.4, 1.6 Hz, 4H), 7.06 (dd, = 8.5, 2.3 Hz, 1H), 4.52 (q, = 3.4 Hz, 1H), 3.97C3.87 (m, 3H), 3.57 (tdd, = 12.9, 4.2, 1.7 Hz, 1H), 3.32 (bs, 1H), 2.20C2.13 (m, 1H), 1.99C1.90 (m, 1H), 1.50 (s, 9H), 1.19 (s, 9H). 13C NMR (126 MHz, CDCl3) 153.43, 140.77, 136.51, 136.42, 128.88, 128.71, 128.55, 128.47, 128.34, 125.97, 123.89, 80.97, 55.52, 50.36, 41.08, 40.00, 29.41, 28.22, 22.48. (= 8.3, 2.1, 1H), 4.53 (t, = 4.6, 1H), 3.95 (s, 2H), 3.94C3.85 (m, 1H), 3.80C3.68 (m, 1H), 3.34 (br s, 1H), 2.51C2.41 (m, 2H), 2.27C2.15 (m, 1H), 2.08C1.97 (m, 1H), 1.74C1.63 (m, 2H), 1.20 (s, 9H), 0.92 Zatebradine hydrochloride (t, = 7.4, 3H). (= 8.2, 2.2.Mice were group-housed and had free access to food and water at all times. mg/kg. EMR2 Plotted as average SEM. Data for 4a from ref (8). Discussion and Conclusions All new analogues across both series sets, excluding 4m, maintained high binding affinity at MOR and exhibited an increased DOR binding affinity when compared to the unsubstituted parent compounds 4a and 15a, presumably due to the carbonyl moiety incorporated into each of the = 0.9, 1H), 7.39 (br s, 1H), 7.35 (dd, = 8.2, 2.2, 1H), 7.29 (t, = 7.4, 2H), 7.23C7.16 (m, 3H), 4.20 (t, = 6.2, 2H), 3.98 (s, 2H), 2.75 (t, = 6.2, 2H), 2.58 (q, = 7.4, 2H), 1.20 (t, = 7.4, 3H). 13C NMR (126 MHz, CDCl3) 194.27, 173.03, 142.21, 140.13, 138.78, 134.63, 128.90, 128.71, 127.62, 126.49, 126.11, 124.44, 43.88, 41.29, 39.62, 27.98, 9.91. 6-Benzyl-1-butyryl-2,3-dihydroquinolin-4(1= 1.3, 1H), 7.39C7.34 (m, 2H), 7.33C7.25 (m, 2H), 7.25C7.16 (m, 3H), 4.21 (t, = 6.2, 2H), 3.99 (s, 2H), 2.76 (t, = 6.2, 2H), 2.54 (t, = 8.0, 2H), 1.79C1.66 (m, 2H), 0.95 (t, = 7.4, 3H). 13C NMR (101 MHz, CDCl3) 194.37, 172.35, 142.31, 140.18, 138.87, 134.71, 128.99, 128.80, 127.77, 126.58, 126.18, 124.55, 43.97, 41.38, 39.82, 36.57, 19.25, 13.94. 6-Benzyl-1-isobutyryl-2,3-dihydroquinolin-4(1= 2.0 Hz, 1H), 7.37C7.25 (m, 4H), 7.25C7.17 (m, 3H), 4.21 (t, = 6.3 Hz, 2H), 3.99 (s, 2H), 3.14 (hept, = 6.7 Hz, 1H), 2.75 (t, = 6.2 Hz, 2H), 1.18 (d, = 6.7 Hz, 6H). 13C NMR (126 MHz, CDCl3) 194.33, 176.97, 142.29, 140.05, 138.84, 134.59, 128.90, 128.87, 128.68, 127.64, 126.46, 126.15, 124.22, 43.90, 41.25, 39.79, 31.13, 19.88. 6-Benzyl-1-(cyclopropanecarbonyl)-2,3-dihydroquinolin-4(1= 2.2, 1H), 7.46 (d, = 8.3, 1H), 7.35 (dd, = 8.4, 2.2, 1H), 7.31C7.26 (m, 2H), 7.22C7.17 (m, 3H), 4.26 (t, = 6.3, 2H), 3.98 (s, 2H), 2.76 (t, = 6.3, 2H), 2.06C1.96 (m, 1H), 1.21C1.15 (m, 2H), 0.91C0.82 (m, 2H). 13C NMR (126 MHz, CDCl3) 194.41, 173.00, 142.45, 140.13, 138.53, 134.49, 128.89, 128.71, 127.74, 126.49, 125.85, 124.09, 43.53, 41.28, 39.70, 13.74, 9.77. 6-Benzyl-1-(cyclobutanecarbonyl)-2,3-dihydroquinolin-4(1= 1.3, 1H), 7.48C7.37 (br s, 1H), 7.35 (dd, = 8.2, 2.2, 1H), 7.29 (t, = 7.5, 2H), 7.24C7.13 (m, 3H), 4.12 (t, = 6.2, 2H), 3.98 (s, 2H), 3.52 (p, = 8.4, 1H), 2.72 (t, = 6.2, 2H), 2.43 (dq, = 11.8, 9.2, 2H), 2.13 (q, = 9.9, 2H), 2.02C1.88 (m, 2H). 13C NMR (126 MHz, CDCl3) 194.09, 174.02, 142.14, 140.14, 138.52, 134.63, 128.85, 128.64, 127.49, 126.41, 125.75, 123.84, 43.78, 41.24, 39.57, 37.95, 25.72, 17.83. Methyl 6-Benzyl-4-oxo-3,4-dihydroquinoline-1(2= 2.1 Hz, 1H), 7.71 (d, = 8.6 Hz, 1H), 7.34 (dd, = 8.6, 2.2 Hz, 1H), 7.29 (t, = 7.5 Hz, 2H), 7.23C7.16 (m, 3H), 4.18 (t, = 6.3 Hz, 2H), 3.97 (s, 2H), 3.84 (s, 3H), 2.76 (t, = 6.3 Hz, 2H). 13C NMR (126 MHz, CDCl3) 193.79, 154.23, 141.74, 140.24, 137.32, 134.79, 128.74, 128.51, 127.13, 126.25, 124.79, 123.58, 53.30, 44.40, 41.09, 38.81. 6-Benzyl-1-(2-methoxyacetyl)-2,3-dihydroquinolin-4(1= 2.2 Hz, 1H), 7.37 (dd, = 8.4, 2.2 Hz, 1H), 7.28 (t, = 7.6 Hz, 2H), 7.23C7.15 (m, 3H), 4.26 (s, 2H), 4.17 (t, = 6.3 Hz, 2H), 3.98 (s, 2H), 3.45 (s, 3H), 2.78 (t, = 6.2 Hz, 2H). 13C NMR (126 MHz, CDCl3) 193.62, 168.07, 141.25, 139.91, 139.02, 134.72, 128.77, 128.58, 128.55, 127.56, 126.37, 125.78, 123.66, 76.74, 71.84, 59.24, 43.95, 41.17, 39.41. 1-Benzoyl-6-benzyl-2,3-dihydroquinolin-4(1= 2.1 Hz, 1H), 7.42C7.34 (m, 3H), 7.31C7.25 (m, 2H), 7.22C7.17 (m, 2H), 7.14C7.10 (m, 1H), 7.08C7.04 (m, 2H), 7.01 (dd, = 8.5, 2.2 Hz, 1H), 6.81 (d, = 8.4 Hz, 1H), 4.21 (t, = 6.3 Hz, 2H), 3.85 (s, 2H), 2.77 (t, = 6.3 Hz, 2H). 13C NMR (126 MHz, CDCl3) 193.73, 170.04, 142.60, 139.99, 138.06, 135.06, 134.31, 130.99, 128.78, 128.58, 128.47, 128.39, 127.38, 126.36, 124.82, 124.63, 45.30, 41.10, 39.50. (= 8.2 Hz, 1H), 7.29C7.21 (m, 2H), 7.20C7.15.HPLC (gradient A): retention time = 38.5. in the mouse WWTW assay following ip administration of 10 mg/kg. Plotted as average SEM. Data for 4a from ref (8). Discussion and Conclusions All new analogues across both series sets, excluding 4m, maintained high binding affinity at MOR and exhibited an increased DOR binding affinity when compared to the unsubstituted parent compounds 4a and 15a, presumably due to the carbonyl moiety incorporated into each of the = 0.9, 1H), 7.39 (br s, 1H), 7.35 (dd, = 8.2, 2.2, 1H), 7.29 (t, = 7.4, 2H), 7.23C7.16 (m, 3H), 4.20 (t, = 6.2, 2H), 3.98 (s, 2H), 2.75 (t, = 6.2, 2H), 2.58 (q, = 7.4, 2H), 1.20 (t, = 7.4, 3H). 13C NMR (126 MHz, CDCl3) 194.27, 173.03, 142.21, 140.13, 138.78, 134.63, 128.90, 128.71, 127.62, 126.49, 126.11, 124.44, 43.88, 41.29, 39.62, 27.98, 9.91. 6-Benzyl-1-butyryl-2,3-dihydroquinolin-4(1= 1.3, 1H), 7.39C7.34 (m, 2H), 7.33C7.25 (m, 2H), 7.25C7.16 (m, 3H), 4.21 (t, = 6.2, 2H), 3.99 (s, 2H), 2.76 (t, = 6.2, 2H), 2.54 (t, = 8.0, 2H), 1.79C1.66 (m, 2H), 0.95 (t, = 7.4, 3H). 13C NMR (101 MHz, CDCl3) 194.37, 172.35, 142.31, 140.18, 138.87, 134.71, 128.99, 128.80, 127.77, 126.58, 126.18, 124.55, 43.97, 41.38, 39.82, 36.57, 19.25, 13.94. 6-Benzyl-1-isobutyryl-2,3-dihydroquinolin-4(1= 2.0 Hz, 1H), 7.37C7.25 (m, 4H), 7.25C7.17 (m, 3H), 4.21 (t, = 6.3 Hz, 2H), 3.99 (s, 2H), 3.14 (hept, = 6.7 Hz, 1H), 2.75 (t, = 6.2 Hz, 2H), 1.18 (d, = 6.7 Hz, 6H). 13C NMR (126 MHz, CDCl3) 194.33, 176.97, 142.29, 140.05, 138.84, 134.59, 128.90, 128.87, 128.68, 127.64, 126.46, 126.15, 124.22, 43.90, 41.25, 39.79, 31.13, 19.88. 6-Benzyl-1-(cyclopropanecarbonyl)-2,3-dihydroquinolin-4(1= 2.2, 1H), 7.46 (d, = 8.3, 1H), 7.35 (dd, = 8.4, 2.2, 1H), 7.31C7.26 (m, 2H), 7.22C7.17 (m, 3H), 4.26 (t, = 6.3, 2H), 3.98 (s, 2H), 2.76 (t, = 6.3, 2H), 2.06C1.96 (m, 1H), 1.21C1.15 (m, 2H), 0.91C0.82 (m, 2H). 13C NMR (126 MHz, CDCl3) 194.41, 173.00, 142.45, 140.13, 138.53, 134.49, 128.89, 128.71, 127.74, 126.49, 125.85, 124.09, 43.53, 41.28, 39.70, 13.74, 9.77. 6-Benzyl-1-(cyclobutanecarbonyl)-2,3-dihydroquinolin-4(1= 1.3, 1H), 7.48C7.37 (br s, 1H), 7.35 (dd, = 8.2, 2.2, 1H), 7.29 (t, = 7.5, 2H), 7.24C7.13 (m, 3H), 4.12 (t, = 6.2, 2H), 3.98 (s, 2H), 3.52 (p, = 8.4, 1H), 2.72 (t, = 6.2, 2H), 2.43 (dq, = 11.8, 9.2, 2H), 2.13 (q, = 9.9, 2H), 2.02C1.88 (m, 2H). 13C NMR (126 MHz, CDCl3) 194.09, 174.02, 142.14, 140.14, 138.52, 134.63, 128.85, 128.64, 127.49, 126.41, 125.75, 123.84, 43.78, 41.24, 39.57, 37.95, 25.72, 17.83. Methyl 6-Benzyl-4-oxo-3,4-dihydroquinoline-1(2= 2.1 Hz, 1H), 7.71 (d, = 8.6 Hz, 1H), 7.34 (dd, = 8.6, 2.2 Hz, 1H), 7.29 (t, = 7.5 Hz, 2H), 7.23C7.16 (m, 3H), 4.18 (t, = 6.3 Hz, 2H), 3.97 (s, 2H), 3.84 (s, 3H), 2.76 (t, = 6.3 Hz, 2H). 13C NMR (126 MHz, CDCl3) 193.79, 154.23, 141.74, 140.24, 137.32, 134.79, 128.74, 128.51, 127.13, 126.25, 124.79, 123.58, 53.30, 44.40, 41.09, 38.81. 6-Benzyl-1-(2-methoxyacetyl)-2,3-dihydroquinolin-4(1= 2.2 Hz, 1H), 7.37 (dd, = 8.4, 2.2 Hz, 1H), 7.28 (t, = 7.6 Hz, 2H), 7.23C7.15 (m, 3H), 4.26 (s, 2H), 4.17 (t, = 6.3 Hz, 2H), 3.98 (s, 2H), 3.45 (s, 3H), 2.78 (t, = 6.2 Hz, 2H). 13C NMR (126 MHz, CDCl3) 193.62, 168.07, 141.25, 139.91, 139.02, 134.72, 128.77, 128.58, 128.55, 127.56, 126.37, 125.78, 123.66, 76.74, 71.84, 59.24, 43.95, 41.17, 39.41. 1-Benzoyl-6-benzyl-2,3-dihydroquinolin-4(1= 2.1 Hz, 1H), 7.42C7.34 (m, 3H), 7.31C7.25 (m, 2H), 7.22C7.17 (m, 2H), 7.14C7.10 (m, 1H), 7.08C7.04 (m, 2H), 7.01 (dd, = 8.5, 2.2 Hz, 1H), 6.81 (d, = 8.4 Hz, 1H), 4.21 (t, = 6.3 Hz, 2H), 3.85 (s, 2H), 2.77 (t, = 6.3 Hz, 2H). 13C NMR (126 MHz, CDCl3) 193.73, 170.04, Zatebradine hydrochloride 142.60, 139.99, 138.06, 135.06, 134.31, 130.99, 128.78, 128.58, 128.47, 128.39, 127.38, 126.36, 124.82, 124.63, 45.30, 41.10, 39.50. (= 8.2 Hz, 1H), 7.29C7.21 (m, 2H), 7.20C7.15 (qd, = 6.5, 5.4, 1.6 Hz, 4H), 7.06 (dd, = 8.5, 2.3 Hz, 1H), 4.52 (q, = 3.4 Hz, 1H), 3.97C3.87 (m, 3H), 3.57 (tdd, = 12.9, 4.2, 1.7 Hz, 1H), 3.32 (bs, 1H), 2.20C2.13 (m, 1H), 1.99C1.90 (m, 1H), 1.50 (s, 9H), 1.19 (s, 9H). 13C NMR (126 MHz, CDCl3) 153.43, 140.77, 136.51, 136.42, 128.88, 128.71, 128.55, 128.47, 128.34, 125.97, 123.89, 80.97, 55.52, 50.36, 41.08, 40.00, 29.41, 28.22, 22.48. (= 8.3, 2.1, 1H), 4.53 (t, = 4.6, 1H), 3.95 (s, 2H), 3.94C3.85 (m, 1H), 3.80C3.68 (m, 1H), 3.34 (br s, 1H), 2.51C2.41 (m, 2H), 2.27C2.15 (m, 1H),.
