Anal

Anal. Opioid antagonists with varying degrees of receptor potency and selectivity have been developed for the opioid receptor. The first highly selective and potent opioid receptor antagonist was norBNI (1).16,17 Continued studies identified 5-GNTI (2) as a more potent and selective opioid antagonist.18-20 In 2001, JDTic (3), an = 9.0 Hz, 1H), 7.10 (m, 4H), 6.71 (m, 2H), 6.60 (d, 6.0 Hz, 1H), 4.42 (m, 1H), 2.32C2.92 (bm, 7H), 2.25 (bt, 1H), 2.05 (m, 1H), 1.92 (bs, 1H), 1.57 (bd, 1H), 1.27 (s, 3H), 1.06 (dd, = 4.8, 2.1 Hz, 6H), 0.55 (d, = 6.9 Hz, 3H). The resulting solid was dissolved in CH2Cl2CMeOH (1:1) and acidified with 1M ethereal HCl. The mixture was concentrated in vacuo, dried to yield 0 then.065 g (23%) of 6 as a white solid: mp 207C211 C. Anal. (C29H37ClN2O3?2 H2O) C,H, N. 6-Hydroxy-1,2,3,4-tetrahydro-naphthalene-2(+)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 6.78 Hz, 3 H), 0.90 (d, = 6.78 Hz, 3 H), 0.93 (d, = 6.78 Hz, 3 H), 1.27 (s, 3 H), 1.55 (d, = 12.81 Hz, 1 H), 1.68C1.89 (m, 2 H), 1.95 (m, 2 H), 2.36C2.81 (m, 12H), 4.02 (ddd, = 9.61, 5.09, 4.90 Hz, 1 H), 6.50 (d, = 2.26 Hz, 1 H), 6.57 (ddd, = 15.26, 8.10, 2.26 Hz, 2 H), 6.70C6.80 (m, 2 H), 6.85 (d, = 8.29 Hz, 1 H), 7.10 (t, = 8.10 Hz, 1 H), 7.81 (br s, 1 H). Anal. (C29H41ClN2O3?0.75 H2O) C, H, N. 6-Hydroxy-1,2,3,4-tetrahydro-naphthalene-2(-)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 7.32 Hz, 3 H), 0.91 (d, = 6.84 Hz, 3 H), 0.95 (d, = 6.84 Hz, 3 H), 1.27C1.30 (s, 3 H), 1.57 (d, = 11.23 Hz, 1 H), 1.75C1.86 (m, 2 H), 1.95C2.03 (m, 2 H), 2.29 (td, = 12.57, 4.15 Hz, 1 H), 2.34C2.41 (m, 1 H), 2.42C2.87 (m, 10 H), 4.02 (dt, = 9.77, 4.88 Hz, 1 H), 6.49 (m, 1 H), 6.52 (dd, = 8.30, 2.44 Hz, 1 H), 6.58 (dd, = 7.81, 1.95 Hz, 1 H), 6.74 (m, 1 H), 6.77 (d, = 7.81 Hz, 1 H), 6.82 (d, = 8.30 Hz, 1 H), 7.10 (t, = 8.06 Hz, 1H). Anal. (C29H41ClN2O3?1.5 H2O) C, H, N. 7-Hydroxy-3,4-dihydro-1= 6Hz, 3H), 0.93 (m, 6H), 1.28 (m, 4H), 1.56 (d, = 12 Hz, 1H), 1.87 (m, 1H), 1.95 (m, 1H), 2.26 (ddd, 1H), 2.41C2.55 (m, 4H), 2.64C2.80 (m, 2H), 2.90C2.96 (dd, = 3, 18 Hz, 1H), 3.99 (m, 1H), 4.14 (dd, = 6, 12 Hz, 1H), 4.84 (d, 1H), 4.87 (d, = 12 Hz, 1H), 6.45 (s, 1H), 6.58 (m, 2H), 6.71 (m, 2H), 6.91 (d, = 9 Hz, 1H), 7.07 (dd, = 9, 9 Hz, 1H). HRMS 467.2908 (M+H)+, predicted 467.2910. 7-Hydroxy-3,4-dihydro-1= 6Hz, 3H), 0.93 (m, 6H), 1.28 (m, 4H), 1.56 (d, = 12 Hz, 1H), 1.87 (m, 1H), 1.95 (m, 1H), 2.26 (ddd, 1H), 2.41C2.55 (m, 4H), 2.64C2.80 (m, 2H), 2.90C2.96 (dd, = 3, 18 Hz, 1H), 3.99 (m, 1H), 4.14 (dd, = 6, 12 Hz, 1H), 4.84 (d, 1H), 4.87 (d, = 12 Hz, 1H), 6.45 (s, 1H), 6.58 (m, 2H), 6.71 (m, 2H), 6.91 (d, = 9 Hz, 1H), 7.07 (dd, = 9, 9 Hz, 1H). HRMS 467.2905 (M+H)+, predicted 467.2910. 7-Hydroxyisothiochroman-3(+)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 12.9 Hz, 1H), 1.64C1.68 (m, 1H), 1.94C1.96 (m, 1H), 2.17C2.47 (m, 4H), 2.58C2.62 (d, = 11.3 Hz, 1H), 2.72C2.75 (d, = 11.3 Hz, 1H), 2.89C2.96 (dd, = 5.3, 15 Hz, 1H), 3.11C3.18 (dd, = 7.54, 14.3 Hz, 1H), 3.62C3.77 (m, 3H), 3.83C3.90 (m, 1H), 6.54C6.65 (m, 3H), 6.71C6.76 (m, 2H), 6.91C6.94 (d, = 8.2 Hz, 1H), 7.06C7.11 (t, = 7.9 Hz, 1H). Anal. (C28H38N2O3S?0.25 H2O) C, H, N. 7-Hydroxyisothiochroman-3(-)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 6.8 Hz, 3H), 0.83C0.85 (d, = 6.8 Hz, 3H), 0.88C0.90 (d, = 6.8 Hz, 3H), 1.06C1.13 (m, 1H), 1.26 (s, 3H), 1.50C1.54 (d, = 12.4 Hz, 1H), 1.79C1.94 (m, 2H), 2.15C2.39 (m, 4H), 2.48.One rat from each group was dosed in succession and the pattern repeated to distribute any effects of time of day across all groups. (cocaine, opiate, alcohol, nicotine, and possibly others),1-7 depression, 1,8-10 anxiety disorders,11 obesity, 12-14 and psychosis disorders.15 Opioid antagonists with varying degrees of receptor selectivity and potency have been developed for the opioid receptor. The first highly selective and potent opioid receptor antagonist was norBNI (1).16,17 Continued studies identified 5-GNTI (2) as a more potent and selective opioid antagonist.18-20 In 2001, JDTic (3), an = 9.0 Hz, 1H), 7.10 (m, 4H), 6.71 (m, 2H), 6.60 (d, 6.0 Hz, 1H), 4.42 (m, 1H), 2.32C2.92 (bm, 7H), 2.25 (bt, 1H), 2.05 (m, 1H), 1.92 (bs, 1H), 1.57 (bd, 1H), 1.27 (s, 3H), 1.06 (dd, = 4.8, 2.1 Hz, 6H), 0.55 (d, = 6.9 Hz, 3H). The resulting solid was dissolved in CH2Cl2CMeOH (1:1) and acidified with 1M ethereal HCl. The mixture was concentrated in vacuo, then dried to yield 0.065 g (23%) of 6 as a white solid: mp 207C211 C. Anal. (C29H37ClN2O3?2 H2O) C,H, N. 6-Hydroxy-1,2,3,4-tetrahydro-naphthalene-2(+)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 6.78 Hz, 3 H), 0.90 (d, = 6.78 Hz, 3 H), 0.93 (d, = 6.78 Hz, 3 H), 1.27 (s, 3 H), 1.55 (d, = 12.81 Hz, 1 H), 1.68C1.89 (m, 2 H), 1.95 (m, 2 H), 2.36C2.81 (m, 12H), 4.02 (ddd, = 9.61, 5.09, 4.90 Hz, 1 H), 6.50 (d, = 2.26 Hz, 1 H), 6.57 (ddd, = 15.26, 8.10, 2.26 Hz, 2 H), 6.70C6.80 (m, 2 H), 6.85 (d, = 8.29 Hz, 1 H), 7.10 (t, = 8.10 Hz, 1 H), 7.81 (br s, 1 H). Anal. (C29H41ClN2O3?0.75 H2O) C, H, N. 6-Hydroxy-1,2,3,4-tetrahydro-naphthalene-2(-)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 7.32 Hz, 3 H), 0.91 (d, = 6.84 Hz, 3 H), 0.95 (d, = 6.84 Hz, 3 H), 1.27C1.30 (s, 3 H), 1.57 (d, = 11.23 Hz, 1 H), 1.75C1.86 (m, 2 H), 1.95C2.03 (m, 2 H), 2.29 (td, = 12.57, 4.15 Hz, 1 H), 2.34C2.41 (m, 1 H), 2.42C2.87 (m, 10 H), 4.02 (dt, = 9.77, 4.88 Hz, 1 H), 6.49 (m, 1 H), 6.52 (dd, = 8.30, 2.44 Hz, 1 H), 6.58 (dd, = 7.81, 1.95 Hz, 1 H), 6.74 (m, 1 H), 6.77 (d, = 7.81 Hz, 1 H), 6.82 (d, = 8.30 Hz, 1 H), 7.10 (t, = 8.06 Hz, 1H). Anal. (C29H41ClN2O3?1.5 H2O) C, H, N. 7-Hydroxy-3,4-dihydro-1= 6Hz, 3H), 0.93 (m, 6H), 1.28 (m, 4H), 1.56 (d, = 12 Hz, 1H), 1.87 (m, 1H), 1.95 (m, 1H), 2.26 (ddd, 1H), 2.41C2.55 (m, 4H), 2.64C2.80 (m, 2H), 2.90C2.96 (dd, = 3, 18 Hz, 1H), 3.99 (m, 1H), 4.14 (dd, = 6, 12 Hz, 1H), 4.84 (d, 1H), 4.87 (d, = 12 Hz, 1H), 6.45 (s, 1H), 6.58 (m, 2H), 6.71 (m, 2H), 6.91 (d, = 9 Hz, 1H), 7.07 (dd, = 9, 9 Hz, 1H). HRMS 467.2908 (M+H)+, predicted 467.2910. 7-Hydroxy-3,4-dihydro-1= 6Hz, 3H), 0.93 (m, 6H), 1.28 (m, 4H), 1.56 (d, = 12 Hz, 1H), 1.87 (m, 1H), 1.95 (m, 1H), 2.26 (ddd, 1H), 2.41C2.55 (m, 4H), 2.64C2.80 (m, 2H), 2.90C2.96 (dd, = 3, 18 Hz, 1H), 3.99 (m, 1H), 4.14 (dd, = 6, 12 Hz, 1H), 4.84 (d, 1H), 4.87 (d, = 12 Hz, 1H), 6.45 (s, 1H), 6.58 (m, 2H), 6.71 (m, 2H), 6.91 (d, = 9 Hz, 1H), 7.07 (dd, = 9, 9 Hz, 1H). HRMS 467.2905 (M+H)+, predicted 467.2910. 7-Hydroxyisothiochroman-3(+)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 12.9 Hz, 1H), 1.64C1.68 (m, 1H), 1.94C1.96 (m, 1H), 2.17C2.47 (m, 4H), 2.58C2.62 (d, = 11.3 Hz, 1H), 2.72C2.75 (d, = 11.3 Hz, 1H), 2.89C2.96 (dd, = 5.3, 15 Hz, 1H), 3.11C3.18 (dd, = 7.54, 14.3 Hz, 1H), 3.62C3.77 (m, 3H), 3.83C3.90 (m, 1H), 6.54C6.65 (m, 3H), 6.71C6.76 (m, 2H), 6.91C6.94 (d, = 8.2 Hz, 1H), 7.06C7.11 (t, = 7.9 Hz, 1H). Anal. (C28H38N2O3S?0.25 H2O) C, H, N. 7-Hydroxyisothiochroman-3(-)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 6.8 Hz, 3H), 0.83C0.85 (d, = 6.8 Hz, 3H), 0.88C0.90 (d, =.(C29H37ClN2O3?2 H2O) C,H, N. 6-Hydroxy-1,2,3,4-tetrahydro-naphthalene-2(+)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 6.78 Hz, 3 H), 0.90 (d, = 6.78 Hz, 3 H), 0.93 (d, = 6.78 Hz, 3 H), 1.27 (s, 3 H), 1.55 (d, = 12.81 Hz, 1 H), 1.68C1.89 (m, 2 H), 1.95 (m, 2 H), 2.36C2.81 (m, 12H), 4.02 (ddd, = 9.61, 5.09, 4.90 Hz, 1 H), 6.50 (d, = 2.26 Hz, 1 H), 6.57 (ddd, = 15.26, 8.10, 2.26 Hz, 2 H), 6.70C6.80 (m, 2 H), 6.85 (d, = 8.29 Hz, 1 H), 7.10 (t, = 8.10 Hz, 1 H), 7.81 (br s, 1 H). Introduction Kappa opioid receptor selective antagonists are of considerable interest as potential pharmacotherapies for addiction (cocaine, opiate, alcohol, nicotine, and possibly others),1-7 depression, 1,8-10 anxiety disorders,11 obesity, 12-14 and psychosis disorders.15 Opioid antagonists with varying degrees of receptor potency and selectivity have been developed for the opioid receptor. The first highly selective and potent opioid receptor antagonist was norBNI (1).16,17 Continued studies identified 5-GNTI (2) as a more potent and selective opioid antagonist.18-20 In 2001, JDTic (3), an = 9.0 Hz, 1H), 7.10 (m, 4H), 6.71 (m, 2H), 6.60 (d, 6.0 Hz, 1H), 4.42 (m, 1H), 2.32C2.92 (bm, 7H), 2.25 (bt, 1H), 2.05 (m, 1H), 1.92 (bs, 1H), 1.57 (bd, 1H), 1.27 (s, 3H), 1.06 (dd, = 4.8, 2.1 Hz, 6H), 0.55 (d, = 6.9 Hz, 3H). The resulting solid was dissolved in CH2Cl2CMeOH (1:1) and acidified with 1M ethereal HCl. The mixture was concentrated in vacuo, then dried to yield 0.065 g (23%) of 6 as a white solid: mp 207C211 C. Anal. (C29H37ClN2O3?2 H2O) C,H, N. 6-Hydroxy-1,2,3,4-tetrahydro-naphthalene-2(+)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 6.78 Hz, 3 H), 0.90 (d, = 6.78 Hz, 3 H), 0.93 (d, = 6.78 Hz, 3 H), 1.27 (s, 3 H), 1.55 (d, = 12.81 Hz, 1 H), 1.68C1.89 (m, 2 H), 1.95 (m, 2 H), 2.36C2.81 (m, 12H), 4.02 (ddd, = 9.61, 5.09, 4.90 Hz, 1 H), 6.50 (d, = 2.26 Hz, 1 H), 6.57 (ddd, = 15.26, 8.10, 2.26 Hz, 2 H), 6.70C6.80 (m, 2 H), 6.85 (d, = 8.29 Hz, 1 H), 7.10 (t, = 8.10 Hz, 1 H), 7.81 (br s, 1 H). Anal. (C29H41ClN2O3?0.75 H2O) C, H, N. 6-Hydroxy-1,2,3,4-tetrahydro-naphthalene-2(-)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 7.32 Hz, 3 H), 0.91 (d, = 6.84 Hz, 3 H), 0.95 (d, = 6.84 Hz, 3 H), 1.27C1.30 (s, 3 H), 1.57 (d, = 11.23 Hz, 1 H), 1.75C1.86 (m, 2 H), 1.95C2.03 (m, 2 H), 2.29 (td, = 12.57, 4.15 Hz, 1 H), 2.34C2.41 (m, 1 H), 2.42C2.87 (m, 10 H), 4.02 (dt, = 9.77, 4.88 Hz, 1 H), 6.49 (m, 1 H), 6.52 (dd, = 8.30, 2.44 Hz, 1 H), 6.58 (dd, = 7.81, 1.95 Hz, 1 H), 6.74 (m, 1 H), 6.77 (d, = 7.81 Hz, 1 H), 6.82 (d, = 8.30 Hz, 1 H), 7.10 (t, = 8.06 Hz, 1H). Anal. (C29H41ClN2O3?1.5 H2O) C, H, N. 7-Hydroxy-3,4-dihydro-1= 6Hz, 3H), 0.93 (m, 6H), 1.28 (m, 4H), 1.56 (d, = 12 Hz, 1H), 1.87 (m, 1H), 1.95 (m, 1H), 2.26 (ddd, 1H), 2.41C2.55 (m, 4H), 2.64C2.80 (m, 2H), 2.90C2.96 (dd, = 3, 18 Hz, 1H), 3.99 (m, 1H), 4.14 (dd, = 6, 12 Hz, 1H), 4.84 (d, 1H), 4.87 (d, = 12 Hz, 1H), 6.45 (s, 1H), 6.58 (m, 2H), 6.71 (m, 2H), 6.91 (d, = 9 Hz, 1H), 7.07 (dd, = 9, 9 Hz, 1H). HRMS 467.2908 (M+H)+, predicted 467.2910. 7-Hydroxy-3,4-dihydro-1= 6Hz, 3H), 0.93 (m, 6H), 1.28 (m, 4H), 1.56 (d, = 12 Hz, 1H), 1.87 (m, 1H), 1.95 (m, 1H), 2.26 (ddd, 1H), 2.41C2.55 (m, 4H), 2.64C2.80 (m, 2H), 2.90C2.96 (dd, = 3, 18 Hz, 1H), 3.99 (m, 1H), 4.14 (dd, = 6, 12 Hz, 1H), 4.84 (d, 1H), 4.87 (d, = 12 Hz, 1H), 6.45 (s, 1H), 6.58 (m, 2H), 6.71 (m, 2H), 6.91 (d, = 9 Hz, 1H), 7.07 (dd, = 9, 9 Hz, 1H). HRMS 467.2905 (M+H)+, predicted 467.2910. 7-Hydroxyisothiochroman-3(+)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 12.9 Hz, 1H), 1.64C1.68 (m, 1H), 1.94C1.96 (m, 1H), 2.17C2.47 (m, 4H), 2.58C2.62 (d, = 11.3 Hz, 1H), 2.72C2.75 (d, = 11.3 Hz, 1H), 2.89C2.96 (dd, = 5.3, 15 Hz, 1H), 3.11C3.18 (dd, = 7.54, 14.3 Hz, 1H), 3.62C3.77 (m, 3H), 3.83C3.90 (m, 1H), 6.54C6.65 (m, 3H), 6.71C6.76 (m, 2H), 6.91C6.94 (d, = 8.2 Hz, 1H), 7.06C7.11 (t, = 7.9 Hz, 1H). Anal. (C28H38N2O3S?0.25 H2O) C, H, N. 7-Hydroxyisothiochroman-3(-)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 6.8 Hz, 3H), 0.83C0.85 (d, = 6.8 Hz, 3H), 0.88C0.90 (d, = 6.8 Hz, 3H), 1.06C1.13 (m, 1H), 1.26 (s, 3H), 1.50C1.54 (d, = 12.4 Hz, 1H), 1.79C1.94 (m, 2H), 2.15C2.39 (m, 4H), 2.48 (brs, 1H), 2.71C2.75 (d, = 11Hz, 1H), 2.97C3.10 (m, 2H), 3.58C3.78 (m, 3H), 3.85C3.91 (m, 1H), 6.57C6.60 (d, = 7.9 Hz, 1H), 6.63 (m, 2H), 6.73 (m,.The solution was heated at 60 C for 2 h, cooled Pinacidil monohydrate to room temperature, and diluted with Pinacidil monohydrate H2O (100 mL). 3, where antagonist activity lasted for three weeks, compound 7a did not show any antagonist activity after one week. Introduction Kappa opioid receptor selective antagonists are of considerable interest as potential pharmacotherapies for addiction (cocaine, opiate, alcohol, nicotine, and possibly others),1-7 depression, 1,8-10 anxiety disorders,11 obesity, 12-14 and psychosis disorders.15 Opioid antagonists with varying degrees of receptor potency and selectivity have been developed for the opioid receptor. The first highly selective and potent opioid receptor antagonist was norBNI (1).16,17 Continued studies identified 5-GNTI (2) as a more potent and selective opioid antagonist.18-20 In 2001, JDTic (3), an = 9.0 Hz, 1H), 7.10 (m, 4H), 6.71 (m, 2H), 6.60 (d, 6.0 Hz, 1H), 4.42 (m, 1H), 2.32C2.92 (bm, 7H), 2.25 (bt, 1H), 2.05 (m, 1H), 1.92 (bs, 1H), 1.57 (bd, 1H), 1.27 (s, 3H), 1.06 (dd, = 4.8, 2.1 Hz, 6H), 0.55 (d, = 6.9 Hz, 3H). The resulting solid was dissolved in CH2Cl2CMeOH (1:1) and acidified with 1M ethereal HCl. The mixture was concentrated in vacuo, then dried to yield 0.065 g (23%) of 6 as a white solid: mp 207C211 C. Anal. (C29H37ClN2O3?2 H2O) C,H, N. 6-Hydroxy-1,2,3,4-tetrahydro-naphthalene-2(+)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 6.78 Hz, 3 H), 0.90 (d, = 6.78 Hz, 3 H), 0.93 (d, = 6.78 Hz, 3 H), 1.27 (s, 3 H), 1.55 (d, = 12.81 Hz, 1 H), 1.68C1.89 (m, 2 H), 1.95 (m, 2 H), 2.36C2.81 (m, 12H), 4.02 (ddd, = 9.61, 5.09, 4.90 Hz, 1 H), 6.50 (d, = 2.26 Hz, 1 H), 6.57 (ddd, = 15.26, 8.10, 2.26 Hz, 2 H), 6.70C6.80 (m, 2 H), 6.85 (d, = 8.29 Hz, 1 H), 7.10 (t, = 8.10 Hz, 1 H), 7.81 (br s, 1 H). Anal. (C29H41ClN2O3?0.75 H2O) C, H, N. 6-Hydroxy-1,2,3,4-tetrahydro-naphthalene-2(-)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 7.32 Hz, 3 H), 0.91 (d, = 6.84 Hz, 3 H), 0.95 (d, = 6.84 Hz, 3 H), 1.27C1.30 (s, 3 H), 1.57 (d, = 11.23 Hz, 1 H), 1.75C1.86 (m, 2 H), 1.95C2.03 (m, 2 H), 2.29 (td, = 12.57, 4.15 Hz, 1 H), 2.34C2.41 (m, 1 H), 2.42C2.87 (m, 10 H), 4.02 (dt, = 9.77, 4.88 Hz, 1 H), 6.49 (m, 1 H), 6.52 (dd, = 8.30, 2.44 Hz, 1 H), 6.58 (dd, = 7.81, 1.95 Hz, 1 H), 6.74 (m, 1 H), 6.77 (d, = 7.81 Hz, 1 H), 6.82 (d, = 8.30 Hz, 1 H), 7.10 (t, = 8.06 Hz, 1H). Anal. (C29H41ClN2O3?1.5 H2O) C, H, N. 7-Hydroxy-3,4-dihydro-1= 6Hz, 3H), 0.93 (m, 6H), 1.28 (m, 4H), 1.56 (d, = 12 Hz, Pinacidil monohydrate Rabbit Polyclonal to GNAT1 1H), 1.87 (m, 1H), 1.95 (m, 1H), 2.26 (ddd, 1H), 2.41C2.55 (m, 4H), 2.64C2.80 (m, 2H), 2.90C2.96 (dd, = 3, 18 Hz, 1H), 3.99 (m, 1H), 4.14 (dd, = 6, 12 Hz, 1H), 4.84 (d, 1H), 4.87 (d, = 12 Hz, 1H), 6.45 (s, 1H), 6.58 (m, 2H), 6.71 (m, 2H), 6.91 (d, = 9 Hz, 1H), 7.07 (dd, = 9, 9 Hz, 1H). HRMS 467.2908 (M+H)+, predicted 467.2910. 7-Hydroxy-3,4-dihydro-1= 6Hz, 3H), 0.93 (m, 6H), 1.28 (m, 4H), 1.56 (d, = 12 Hz, 1H), 1.87 (m, 1H), 1.95 (m, 1H), 2.26 (ddd, 1H), 2.41C2.55 (m, 4H), 2.64C2.80 (m, 2H), 2.90C2.96 (dd, = 3, 18 Hz, 1H), 3.99 (m, 1H), 4.14 (dd, = 6, 12 Hz, 1H), 4.84 (d, 1H), 4.87 (d, = 12 Hz, 1H), 6.45 (s, 1H), 6.58 (m, 2H), 6.71 (m, 2H), 6.91 (d, = 9 Hz, 1H), 7.07 (dd, = 9, 9 Hz, 1H). HRMS 467.2905 (M+H)+, predicted 467.2910. 7-Hydroxyisothiochroman-3(+)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 12.9 Hz, 1H), 1.64C1.68 (m, 1H), 1.94C1.96 (m, 1H), 2.17C2.47 (m, 4H), 2.58C2.62 (d, = 11.3 Hz, 1H), 2.72C2.75 (d, = 11.3 Hz, 1H), 2.89C2.96 (dd, = 5.3, 15 Hz, 1H), 3.11C3.18 (dd, = 7.54, 14.3 Hz, 1H), 3.62C3.77 (m, 3H), 3.83C3.90 (m, 1H), 6.54C6.65 (m, 3H), 6.71C6.76 (m, 2H), 6.91C6.94 (d, = 8.2 Hz, 1H), 7.06C7.11 (t, = 7.9 Hz, 1H). Anal. (C28H38N2O3S?0.25 H2O) C, H, N. 7-Hydroxyisothiochroman-3(-)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 6.8 Hz, 3H), 0.83C0.85 (d, = 6.8 Hz, 3H), 0.88C0.90 (d, = 6.8 Hz, 3H), 1.06C1.13 (m, 1H), 1.26 (s, 3H), 1.50C1.54 (d, = 12.4 Hz, 1H), 1.79C1.94 (m, 2H), 2.15C2.39 (m, 4H), 2.48 (brs, 1H), 2.71C2.75 (d, =.A Ke was had by This compound = 0.18 was and nM 37- and 248-fold selective for the relative to the and opioid receptors, respectively. U50,488-induced diuresis after s.c. administration in rats. In contrast to 3, where antagonist activity lasted for three weeks, compound 7a did not show any antagonist activity after one week. Introduction Kappa opioid receptor selective antagonists are of considerable interest as potential pharmacotherapies for addiction (cocaine, opiate, alcohol, nicotine, and possibly others),1-7 depression, 1,8-10 anxiety disorders,11 obesity, 12-14 and psychosis disorders.15 Opioid antagonists with varying degrees of receptor potency and selectivity have been developed for the opioid receptor. The first highly selective and potent opioid receptor antagonist was norBNI (1).16,17 Continued studies identified 5-GNTI (2) as a more potent and selective opioid antagonist.18-20 In 2001, JDTic (3), an = 9.0 Hz, 1H), 7.10 (m, 4H), 6.71 (m, 2H), 6.60 (d, 6.0 Hz, 1H), 4.42 (m, 1H), 2.32C2.92 (bm, 7H), 2.25 (bt, 1H), 2.05 (m, 1H), 1.92 (bs, 1H), 1.57 (bd, 1H), 1.27 (s, 3H), 1.06 (dd, = 4.8, 2.1 Hz, 6H), 0.55 (d, = 6.9 Hz, 3H). The resulting solid was dissolved in CH2Cl2CMeOH (1:1) and acidified with 1M ethereal HCl. The mixture was concentrated in vacuo, then dried to yield 0.065 g (23%) of 6 as a white solid: mp 207C211 C. Anal. (C29H37ClN2O3?2 H2O) C,H, N. 6-Hydroxy-1,2,3,4-tetrahydro-naphthalene-2(+)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 6.78 Hz, 3 H), 0.90 (d, = 6.78 Hz, 3 H), 0.93 (d, = 6.78 Hz, 3 H), 1.27 (s, 3 H), 1.55 (d, = 12.81 Hz, 1 H), 1.68C1.89 (m, 2 H), 1.95 (m, 2 H), 2.36C2.81 (m, 12H), 4.02 (ddd, = 9.61, 5.09, 4.90 Hz, 1 H), 6.50 (d, = 2.26 Hz, 1 Pinacidil monohydrate H), 6.57 (ddd, = 15.26, 8.10, 2.26 Hz, 2 H), 6.70C6.80 (m, 2 H), 6.85 (d, = 8.29 Hz, 1 H), 7.10 (t, = 8.10 Hz, 1 H), 7.81 (br s, 1 H). Anal. (C29H41ClN2O3?0.75 H2O) C, H, N. 6-Hydroxy-1,2,3,4-tetrahydro-naphthalene-2(-)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 7.32 Hz, 3 H), 0.91 (d, = 6.84 Hz, 3 H), 0.95 (d, = 6.84 Hz, 3 H), 1.27C1.30 (s, 3 H), 1.57 (d, = 11.23 Hz, 1 H), 1.75C1.86 (m, 2 H), 1.95C2.03 (m, 2 H), 2.29 (td, = 12.57, 4.15 Hz, 1 H), 2.34C2.41 (m, 1 H), 2.42C2.87 (m, 10 H), 4.02 (dt, = 9.77, 4.88 Hz, 1 H), 6.49 (m, 1 H), 6.52 (dd, = 8.30, 2.44 Hz, 1 H), 6.58 (dd, = 7.81, 1.95 Hz, 1 H), 6.74 (m, 1 H), 6.77 (d, = 7.81 Hz, 1 H), 6.82 (d, = 8.30 Hz, 1 H), 7.10 (t, = 8.06 Hz, 1H). Anal. (C29H41ClN2O3?1.5 H2O) C, H, N. 7-Hydroxy-3,4-dihydro-1= 6Hz, 3H), 0.93 (m, 6H), 1.28 (m, 4H), 1.56 (d, = 12 Hz, 1H), 1.87 (m, 1H), 1.95 (m, 1H), 2.26 (ddd, 1H), 2.41C2.55 (m, 4H), 2.64C2.80 (m, 2H), 2.90C2.96 (dd, = 3, 18 Hz, 1H), 3.99 (m, 1H), 4.14 (dd, = 6, 12 Hz, 1H), 4.84 (d, 1H), 4.87 (d, = 12 Hz, 1H), 6.45 (s, 1H), 6.58 (m, 2H), 6.71 (m, 2H), 6.91 (d, = 9 Hz, 1H), 7.07 (dd, = 9, 9 Hz, 1H). HRMS 467.2908 (M+H)+, predicted 467.2910. 7-Hydroxy-3,4-dihydro-1= 6Hz, 3H), 0.93 (m, 6H), 1.28 (m, 4H), 1.56 (d, = 12 Hz, 1H), 1.87 (m, 1H), 1.95 (m, 1H), 2.26 (ddd, 1H), 2.41C2.55 (m, 4H), 2.64C2.80 (m, 2H), 2.90C2.96 (dd, = 3, 18 Hz, 1H), 3.99 (m, 1H), 4.14 (dd, = 6, 12 Hz, 1H), 4.84 (d, 1H), 4.87 (d, = 12 Hz, 1H), 6.45 (s, 1H), 6.58 (m, 2H), 6.71 (m, 2H), 6.91 (d, = 9 Hz, 1H), 7.07 (dd, = 9, 9 Hz, 1H). HRMS 467.2905 (M+H)+, predicted 467.2910. 7-Hydroxyisothiochroman-3(+)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 12.9 Hz, 1H), 1.64C1.68 (m, 1H), 1.94C1.96 (m, 1H), 2.17C2.47 (m, 4H), 2.58C2.62 (d, = 11.3 Hz, 1H), 2.72C2.75 (d, = 11.3 Hz, 1H), 2.89C2.96 (dd, = 5.3, 15 Hz, 1H), 3.11C3.18 (dd, = 7.54, 14.3 Hz, 1H), 3.62C3.77 (m, 3H), 3.83C3.90 (m, 1H), 6.54C6.65 (m, 3H), 6.71C6.76 (m, 2H), 6.91C6.94 (d, = 8.2 Hz, 1H), 7.06C7.11 (t, = 7.9 Hz, 1H). Anal. (C28H38N2O3S?0.25 H2O) C, H, N. 7-Hydroxyisothiochroman-3(-)-carboxylic acid-{1-[4-(3-hydroxyphenyl)-(3= 6.8 Hz, 3H), 0.83C0.85 (d, = 6.8 Hz, 3H), 0.88C0.90 (d, = 6.8 Hz, 3H), 1.06C1.13 (m, 1H), 1.26 (s, 3H), 1.50C1.54 (d, = 12.4 Hz, 1H), 1.79C1.94 (m, 2H), 2.15C2.39 (m, 4H), 2.48 (brs, 1H), 2.71C2.75 (d, = 11Hz, 1H), 2.97C3.10 (m, 2H), 3.58C3.78 (m, 3H), 3.85C3.91 (m, 1H), 6.57C6.60 (d, = 7.9 Hz, 1H), 6.63 (m, 2H), 6.73 (m, 2H), 6.95C6.98 (d, =.