Table 3. Antinociceptive Potencies of 6-Amino Acid (2–21)- and 6-Dipeptide-Substituted Derivatives (22a and 23a), Reference Compound 1 and Morphine in the Writhing Assay in Mice after sc Administrationa.
| compd | amino acid substitution at position 6 | ED50 (μg/kg, sc) (95% CI) |
|---|---|---|
| morphine | 437 (249–768) | |
| 1 | 3.26 (1.24–8.52) | |
| 2a | α-Gly | 35.7 (15.2–84.0) |
| 2b | β-Gly | 27.5 (11.0–68.7) |
| 3a | α-l-Ala | 16.0 (5.45–47.0) |
| 3b | β-l-Ala | 86.3 (49.0–152) |
| 4a | α-l-Phe | 31.1 (14.3–67.7) |
| 4b | β-l-Phe | 579 (268–1252) |
| 5a | α-Gly | 36.1 (15.1–84.4) |
| 5b | β-Gly | 41.6 (15.5–112) |
| 6a | α-l-Ser | 32.1 (15.8–65.1) |
| 7b | β-l-Val | 117 (44.1–312) |
| 8a | α-l-Lys | 20.6 (10.1–41.8) |
| 9a | α-l-Tyr | 14.6 (5.15–41.7) |
| 10b | β-l-Trp | 92.7 (37.5–229) |
| 11a | α-l-Asn | 15.2 (6.89–33.3) |
| 13a | α-l-Asp | 38.2 (16.4–88.9) |
| 14a | α-l-Glu | 36.1 (16.3–79.6) |
| 16b | β-d-Val | 14.0 (5.90–33.3) |
| 17a | α-d-Phe | 18.1 (8.37–39.2) |
| 17b | β-d-Phe | 250 (120–517) |
| 18a | α-l-Chg | 20.6 (4.33–98.2) |
| 19a | α-l-Abu | 17.5 (5.13–59.6) |
| 20a | α-β-Ala | 31.2 (13.2–73.9) |
| 21a | α-GABA | 41.9 (22.6–77.8) |
| 22a | β-l-Val-l-Tyr | 178 (58.0–545) |
| 23a | β-Gly-Gly | 104 (58.5–185) |
a
Groups of mice were administered sc test compound or saline (control), and evaluated in the acetic acid-induced writhing assay. Each compound was tested in at least three doses (n = 6–7 mice per dose). Inhibition of the writhing response was assessed 30 min after drug administration, and ED50 values and 95% confidence intervals (CI in parentheses) were calculated from dose–response curves.