2^′, 6^′-Dimethylphenylalanine : A Useful Aromatic Amino Acid Surrogate for Tyr or Phe Residue in Opioid Peptides

Table 1

Opioid receptor-binding affinity and biological activities of opioid peptide analogs containing Dmp at position 3/4.

Peptide	Receptor binding affinity, 𝐾𝑖±S. E. (nM)		𝛿/μ	μ/𝛿	GPI (μ)	MVD (𝛿)	MVD/GPI	GPI/MVD
	μ ^a	𝛿^b			IC50 (nM)	IC50 (nM)
(1) Leu-enkephalin
Tyr-Gly-Gly-Phe-Leu (ENK)	2.42 ± 0.93	1.43 ± 0.71	—	1.69	103 ± 30	22.2 ± 4.3	—	4.64
[Dmp^4]ENK  (10)	1.25 ± 0.29	17.7 ± 4.2	—	0.07	808 ± 101	624 ± 103	—	1.29
[D-Dmp^4]ENK  (11)	2505 ± 169	8924 ± 4098	—	0.28	>10,000	>10,000	—	—
[Dmt^1]ENK^c	0.0068 ± 0.003	0.031 ± 0.011	—	0.22	0.55 ± 0.17	0.17 ± 0.02	—	3.24
[Dmt^1, Dmp^4]ENK (12)	0.030 ± 0.011	0.1 58 ± 0.034	—	0.19	2.00 ± 0.51	1.45 ± 0.26	—	1.38
[Dmt^1, D-Dmp^4]ENK  (13)	5.61 ± 0.59	40.9 ± 11.5	—	0.14	>10,000^d	>10,000^e
(2) Endomorphin-2
Tyr-Pro-Phe-Phe-NH2 (EM2)	0.557 ± 0.306	14,070 ± 3346	25260	—	10.5 ± 1.2	317 ± 65	30.2	—
[Dmp^3]EM2  (14)	0.0304 ± 0.0208	1063 ± 336	34967	—	0.378 ± 0.104	l.39 ± 0.17	3.68	—
[D-Dmp^3]EM2  (15)	2.4 ± 0.56	4169 ± 954	1737	—	30.4 ± 2.8	187 ± 30	6.15	—
[Dmp^4]EM2 (16)	13.2 ± 1.9	7624 ± 2571	578	—	196 ± 40	320 ± 55	1.63	—
[D-Dmp^4]EM2 (17)	106 ± 20	1765 ± 834	17	—	587 ± 119	2267 ± 603	3.86	—
(3) Demrophin/deltorphin
Dermorphin (DM)	0.092 ± 0.024	192 ± 51	2087	—	3.74 ± 0.57	34.4 ± 4.8	9.2	—
[Dmp^3]DM  (18)	0.00054 ± 0.00021	45.7 ± 11.8	84630	—	1.21 ± 0.23	4.62 ± 0.82	3.8	—
[D-Dmp^3]DM  (19)	4.43 ± 1.85	3300 ± 702	745	—	44.4 ± 6.1	358 ± 45	8.1	—
Deltorphin 11 (DT)	314 ± 53	0.0226 ± 0.0077	—	13894	5437 ± 812	0.582 ± 0.029	—	9342
[Dmp^3]DT  (20)	1098 ± 111	0.00105 ± 0.00043	—	1045714	6705 ± 992	0.022 ± 0.003	—	304772
[D-Dmp^3]DT  (21)	1956 ± 177	111 ± 17	—	18	8214 ± 872	145 ± 15	—	56
(4) Dermorphin-relative short peptide
Tyr-D-Arg-Phe-βAla-NH2 (YRFB)	0.172 ± 0.025	482 ± 121	2802	—	5.31 ± 0.72	116 ± 18	21.8	—
[Dmp^3]YRFB  (22)	0.0350 ± 0.0167	544 ± 143	15543	—	1.67 ± 0.24	27.9 ± 5.0	16.7	—
[D-Dmp^3]YRFB (23)	0.0618 ± 0.0109	>2823	>45679	—	19.8 ± 1.9	305 ± 53	15.4	—

^aVersus [³H]DAMGO. bVersus [³H]DT. ^cData cited from [39]. dAntagonism was shown with pA2 = 6.90 against EM2. eAntagonism was shown with pA2 = 5.57 against DT.