Table 1. Binding Affinities at the Opioid Receptors and Calculated Physicochemical Properties of 6-Amino Acid (2–21)- and 6-Dipeptide-Substituted Derivatives (22a/b and 23a), and Reference Compound 1.

		opioid receptor binding Ki (nM)a				physicochemical propertiesb
compd	amino acid substitution at position 6	MOR	DOR	KOR	Ki ratio MOR/DOR/KOR	c log D7.4
1c		0.10 ± 0.01	4.80 ± 0.22	10.2 ± 2.0	1/48/102	0.48
2ac	α-Gly	0.89 ± 0.09	15.4 ± 1.4	43.2 ± 7.0	1/7/49	–3.35
2bc	β-Gly	0.83 ± 0.02	7.86 ± 0.64	44.8 ± 0.1	1/9.5/54	–3.35
3ac	α-l-Ala	0.77 ± 0.09	26.9 ± 0.8	142 ± 43	1/35/184	–2.81
3bc	β-l-Ala	1.90 ± 0.08	7.71 ± 0.94	63.7 ± 7.8	1/4.1/34	–2.81
4ac	α-l-Phe	0.95 ± 0.07	3.67 ± 0.32	28.5 ± 4.2	1/3.9/30	–1.13
4bc	β-l-Phe	2.58 ± 0.09	1.03 ± 0.13	151 ± 17	1/0.4/59	–1.13
5ad	α-Gly	0.19 ± 0.02	0.22 ± 0.02	0.73 ± 0.01	1/1.2/3.8	–0.85
5bd	β-Gly	0.16 ± 0.02	0.19 ± 0.01	0.81 ± 0.03	1/1.2/5.1	–0.85
6a	α-l-Ser	2.21 ± 0.02	5.32 ± 0.39	196 ± 24	1/2.4/89	–3.89
6b	β-l-Ser	2.14 ± 0.03	5.29 ± 0.31	152 ± 15	1/2.5/71	–3.89
7a	α-l-Val	3.16 ± 0.25	3.91 ± 0.30	325 ± 19	1/1.2/103	–1.94
7b	β-l-Val	3.04 ± 0.12	3.52 ± 0.04	305 ± 39	1/1.2/100	–1.94
8a	α-l-Lys	0.19 ± 0.04	1.27 ± 0.42	12.6 ± 1.3	1/6.7/66	–5.57
8b	β-l-Lys	0.53 ± 0.09	3.34 ± 0.46	33.7 ± 4.1	1/6.3/64	–5.57
9a	α-l-Tyr	0.83 ± 0.04	2.18 ± 0.98	39.5 ± 0.2	1/2.6/48	–1.41
9b	β-l-Tyr	3.20 ± 0.55	3.89 ± 0.64	186 ± 33	1/1.2/58	–1.41
10a	α-l-Trp	0.36 ± 0.01	1.02 ± 0.12	25.1 ± 9.3	1/2.8/70	–1.03
10b	β-l-Trp	0.65 ± 0.09	1.19 ± 0.40	8.66 ± 0.64	1/1.8/13	–1.03
11a	α-l-Asn	1.17 ± 0.07	3.37 ± 0.21	74.0 ± 9.7	1/2.9/63	–4.29
11b	β-l-Asn	1.26 ± 0.05	2.25 ± 0.11	103 ± 10	1/1.8/82	–4.29
12a	α-l-Gln	3.24 ± 0.14	5.13 ± 0.52	351 ± 66	1/1.6/108	–4.04
12b	β-l-Gln	2.48 ± 0.30	4.87 ± 0.76	290 ± 3	1/2.0/117	–4.04
13a	α-l-Asp	1.36 ± 0.05	14.6 ± 3.6	50.2 ± 9.2	1/11/37	–5.64
13b	β-l-Asp	3.42 ± 0.05	22.6 ± 2.2	351 ± 43	1/6.6/103	–5.64
14a	α-l-Glu	1.45 ± 0.09	9.03 ± 0.70	87.2 ± 4.2	1/6.2/60	–5.39
14b	β-l-Glu	11.6 ± 0.7	7.64 ± 0.64	1252 ± 70	1/0.7/108	–5.39
15a	α-d-Ala	0.69 ± 0.11	10.4 ± 0.01	71.5 ± 9.6	1/15/104	–2.81
15b	β-d-Ala	1.48 ± 0.08	11.3 ± 0.9	142 ± 33	1/7.6/96	–2.81
16a	α-d-Val	1.70 ± 0.09	1.93 ± 0.24	202 ± 3	1/1.1/119	–1.94
16b	β-d-Val	1.02 ± 0.07	1.68 ± 0.16	159 ± 17	1/1.6/156	–1.94
17a	α-d-Phe	0.61 ± 0.01	3.69 ± 0.59	76.4 ± 9.3	1/6.0/125	–1.13
17b	β-d-Phe	1.28 ± 0.38	1.19 ± 0.13	139 ± 23	1/0.9/109	–1.13
18a	α-l-Chg	1.23 ± 0.20	14.3 ± 0.09	177 ± 30	1/12/144	–1.26
18b	β-l-Chg	1.66 ± 1.04	1.30 ± 0.16	118 ± 23	1/0.8/71	–1.26
19a	α-l-Abu	0.76 ± 0.19	37.5 ± 3.4	144 ± 7	1/49/189	–2.34
19b	β-l-Abu	1.83 ± 0.04	1.30 ± 0.24	201 ± 10	1/0.7/110	–2.34
20a	α-β-Ala	1.30 ± 0.08	60.0 ± 1.9	182 ± 8	1/46/140	–3.18
20b	β-β-Ala	1.04 ± 0.04	13.9 ± 1.7	71.4 ± 4.6	1/13/69	–3.18
21a	α-GABA	0.77 ± 0.07	12.5 ± 0.7	45.6 ± 4.4	1/16/59	–2.93
21b	β-GABA	1.41 ± 0.13	6.61 ± 0.67	147 ± 13	1/4.7/104	–2.93
22a	α-l-Val-l-Tyr	0.82 ± 0.13	1.19 ± 0.42	69.0 ± 2.5	1/1.5/84	–1.02
22b	β-l-Val-l-Tyr	0.44 ± 0.01	1.38 ± 0.22	390 ± 49	1/3.1/886	–1.02
23a	β-Gly-Gly	4.62 ± 0.09	7.52 ± 0.43	203 ± 34	1/1.6/44	–4.27

^aDetermined in competition radioligand binding assays using rat brain membranes (MOR and DOR) and guinea-pig brain membranes (KOR). Values represent the mean ± SEM of three to four independent experiments each performed in duplicate.

^bCalculated using the MarvinSketch 18.8 (ChemAxon).

^cData from ref (44).

^dData from ref (49).