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ment spectroscopy (TOCSY, ROESY). These results indicated that the

average preferred solution conformation of both peptides was characterized by all-trans peptide bonds. The results of temperature-dependence

studies of the amide proton chemical shifts in conjunction with those of

the molecular mechanics studies indicated that the two analogues had

backbone conformations that were both stabilized by Tyr1-COÁÁÁHNPhe3 (or 2-Nal3) and D-Orn2-COÁÁÁHNy-D-Orn2 hydrogen bonds. Furthermore, ROESY experiments revealed a close proximity between the

aromatic moiety of the 3-position residue and the pyrrolidine ring of the


D-Pro residue in these two compounds. The comparison of all calculated

low-energy conformations with the various proton NMR parameters led

to proposals for the solution conformation of these two peptides (Fig. 4).

Inspection of the structures reveals that the Phe3- and 2-Nal3analogues have similar backbone conformations and the same side chain

orientation at the 3 position. These results suggest that the y-antagonist

Figure 4 Proposed solution conformations of H-Tyr-c-[-D-Orn-2-Nal-D-ProGly-] (left panel) and H-Tyr-c-[D-Orn-Phe-D-Pro-Gly-] (right panel).

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

properties of the 2-Nal3 analogue may not be due to a difference in its

overall conformation in comparison to the Phe3 analogue but rather may

be the result of a direct interference of the 2-naphthyl moiety per se at the

receptor binding site, preventing proper alignment of the peptide such as

required for signal transduction.


y-Opioid agonists are known to produce analgesic effects and look

promising because they induce less tolerance and physical dependence

than morphine, no respiratory depression, and few or no adverse

gastrointestinal effects [65,66]. Selective peptide y agonists currently

available include the enkephalin analogues H-Tyr-D-Thr-Gly-Phe-LeuThr-OH (DTLET), H-Tyr-c[D-Pen-Gly-Phe-D-Pen]OH (DPDPE), and

H-Tyr-c[D-Cys-Phe-D-Pen-OH]OH (JOM-13), as well a the deltorphins

H-Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2 (dermenkephalin), H-Tyr-DAla-Phe-Asp-Val-Val-Gly-NH2 (deltorphin I), and H-Tyr-D-Ala-PheGlu-Val-Val-Gly-NH2 (deltorphin II) (for reviews, see Refs. 20 and 21).

However, these peptides are of relatively large molecular size and for this

reason their ability to cross the BBB is very limited. Nonpeptide y agonists

that were developed in the early to mid-1990s include the racemic compound BW373U86 [67] and its chemically modified enantiomer SNC80

[68], as well as the compound TAN-67 [69]. However, BW373U86 produced significant toxicity, manifested behaviorally as convulsions and

barrel rolling, in mice [70], and TAN-67 showed no significant antinociceptive activity in the mouse tail flick test [69]. Evidently, there is still a need

for the development of new potent y opioid agonists of low molecular

weight and high lipophilicity.

In an effort to increase the moderate y-agonist potency and the yreceptor selectivity of the dipeptide H-Tyr-Tic-NH-(CH2)2-Ph [61], structural modifications of the C-terminal phenylethyl group were performed

by introduction of an additional substituent either in ortho position of the

phenyl ring or at the h carbon [44] (Table 4). The analogue H-Tyr-Tic-NH(CH2)2-Ph(o-Cl) was a 10-fold more potent y agonist than the parent

peptide in the MVD assay and was five times more y-receptor selective.

Introduction of a second phenyl group at the h carbon of the phenylethylamine moiety led to the compound H-Tyr-Tic-NH-CH2-CH(Ph)2, with 20fold increased y-agonist potency and 2-fold improved y selectivity. The

corresponding N-methylated analogue, Tyr(NMe)-Tic-NH-CH2-CH(Ph)2

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Table 4 In Vitro Opioid Activities of Dipeptide y-Opioid Agonists




K yi


K Ai


K Ai /K yi





H-Tyr-Tic-NH-CH2-CH(Ph)COOEt (I)

H-Tyr-Tic-NH-CH2-CH(Ph)COOEt (II)





































Determined in the MVD assay.

Binding assay based on displacement of [3H]DSLET (y-selective) and [3H]DAMGO

(A-selective) from rat brain membrane binding sites.

displayed subnanomolar y-agonist potency and still marked y-receptor

selectivity. One of the isomers (I) of H-Tyr-Tic-NH-CH2-CH(Ph)COOEt

was also found to be a potent y agonist with very high preference for y

receptors over A receptors. An analogue containing 2V-hydroxy,6V-methyltyrosine (Hmt) in place of Tyr1, H-Hmt-Tic-NH-CH2-CH(Ph)2, turned

out to be particularly remarkable because it showed both subnanomolar y

agonist potency (IC50 = 0.630 nM) and very high y-receptor selectivity

(K Ai /K yi = 835). In a direct comparison under identical assay conditions,

this compound was 8 times more potent than the well-known y agonist

DPDPE and 15 times more y selective. None of these compounds had

significant binding affinity for n-opioid receptors. From these results it can

be concluded that the dipeptide derivatives described here represent a new

class of potent and selective y-opioid agonists. It is expected that these

compounds should be able to cross the BBB to some extent because of their

low molecular weight and high lipophilicity. Therefore, they have potential

as centrally acting analgesics that may produce fewer side effects than the

currently used A type opiates.


Application of the concept of conformational restriction to opioid peptides

has produced fruitful results, insofar as peptide analogues and mimetics

with interesting opioid activity profiles and high stability against enzymatic

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

degradation were obtained. The conformationally restricted analogues

that were developed were amenable to meaningful conformational analysis

permitting the elaboration of models of the bioactive conformation at the A

or y receptor.

The multiple conformational restriction of dermorphin-related tetrapeptide analogues that was performed represents a rational design of

opioid peptidomimetics characterized by a high degree of structural rigidification. This is indicated by the fact that the A-selective agonist H-Hat-DOrn-Aic-Glu-NH2 contains only two freely rotatable bonds, whereas there

are 14 freely rotatable bonds in [Leu5]enkephalin.

The discovery of the TIP(P) peptides and their further structural

modification led to y opioid antagonists with unprecedented potency and

selectivity. The observation that very subtle structural modifications of

these flexible and hydrophobic peptides in some cases converted a y

antagonist into a y agonist and vice versa is most intriguing and unique

in the peptide field. This behavior may be explained with changes in the

patterns of aromatic ring clustering in these hydrophobically collapsed

molecules as a consequence of the minor structural alterations (introduction of a halogen substituent, peptide bond reduction, saturation of an

aromatic ring, etc.) that were performed. The TIP(P) peptides are of

therapeutic interest because y antagonists have been shown to attenuate

the development of morphine tolerance and dependence [56,57] and to

have an immunosuppressive effect [71].

The three prototype mixed A agonist/y antagonists described in this

chapter have excellent potential as analgesics with low propensity to

produce tolerance and dependence. The pseudotetrapeptide DIPPNH2[C] has already been shown to produce a potent analgesic effect, less

tolerance than morphine, and no physical dependence upon chronic

administration. In preliminary experiments, the tetrapeptides DIPP-NH2

and DIPP-NH2[C] were shown to cross the BBB to some extent, but

further structural modifications need to be performed in order to improve

the BBB penetration of these compounds. The Tyr-Tic dipeptide derivatives can also be expected to penetrate into the central nervous system

because they are relatively small, lipophilic molecules. In this context, it is

of interest to point out that the structurally related dipeptide H-Dmt-DAla-NH-(CH2)3-Ph (SC-39566), a plain A-opioid agonist, produced antinociception in the rat by subcutaneous and oral administration [72]. As

indicated by the results of the NMR and molecular mechanics studies, the

conformation of the cyclic h-casomorphin analogue H-Tyr-c[-D-Orn-2Nal-D-Pro-Gly-] is stabilized by intramolecular hydrogen bonds. Therej


Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

fore, this mixed A agonist/y antagonist has a reduced capacity for intermolecular hydrogen bonding with water molecules and, consequently,

should have a reasonable chance to cross the BBB as well.

The dipeptide y agonists may turn out to be interesting pharmacological tools, since some of them are more potent and more selective than

the y agonists currently in use. Furthermore, these compounds represent a

new class of y agonists and have potential for pain treatment because they

may also be small enough and lipophilic enough to cross the BBB and to

produce a centrally mediated analgesic effect.


The work described in this chapter was supported by operating grants

from the Medical Research Council of Canada (MT-5655) and the National Institute on Drug Abuse (DA-04443).


1. Schiller PW, DiMaio J. Opiate receptor subclasses differ in their conformational requirements. Nature (London) 1982; 297:74–76.

2. Martin WR, Eades CJ, Thompson GA, Huppler RA, Gilbert PE. The effects

of morphine- and nalorphine-like drugs in the nondependent and morphinedependent chronic spinal dog. J Pharmacol Exp Ther 1976; 197:517–523.

3. Lord JAH, Waterfield AA, Hughes, J, Kosterlitz HW. Endogenous opioid peptides: multiple agonists and receptors. Nature (London) 1977; 267:


4. Clark JA, Liu L, Price M, Hersh B, Edelson M, Pasternak GW. Kappa

opiate receptor multiplicity: evidence for two U50,488-sensitive n1 subtypes

and a novel n3 subtype. J Pharmacol Exp Ther 1989; 251:461–468.

5. Jiang Q, Takemori AE, Sultana M, Portoghese PS, Bowen BD, Mosberg

HI, Porreca F. Differential antagonism of opioid delta antinociception by

[D-Ala2,Leu5,Cys6]enkephalin and naltrindole 5V-isothiocyanate: evidence

for delta receptor subtypes. J Pharmacol Exp Ther 1991; 257:1069–1075.

6. Evans CJ, Keith Jr., DE, Morrison H, Magendzo K, Edwards RH. Cloning of a delta opioid receptor by functional expression. Science 1992; 258:


7. Kieffer BL, Befort K, Gaveriaux-Ruff C, Hirth CG. The y-opioid receptor:

isolation of a cDNA by expression cloning and pharmacological characterization. Proc Natl Acad Sci USA 1992; 89:12048–12052.

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

8. Yasuda K, Raynor K, Kong H, Breder CD, Takeda J, Reisine T, Bell GI.

Cloning and functional comparison of n and y opioid receptors from mouse

brain. Proc Natl Acad Sic USA 1993; 90:6736–6740.

9. Chen Y, Mestek A, Liu J, Hurley JA, Yu L. Molecular cloning and

functional expression of a A-opioid receptor from rat brain. Mol Pharmacol

1993; 44:8–12.

10. Pogozheva ID, Lomize AL, Mosberg HI. Opioid receptor three-dimensional

structures from distance geometry calculations with hydrogen bonding

constraints. Biophys J 1998; 75:612–634.

11. Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris

RH. Identification of two related pentapeptides from the brain with potent

opiate agonist activity. Nature (London) 1975; 258:577579.

12. Hoăllt V. Opioid peptide processing and receptor selectivity, Annu Rev

Pharmacol Toxicol 1986; 26:59–77.

13. Zadina JE, Hackler L, Ge LJ, Kastin AJ. A potent and selective endogenous

agonist for the mu opiate receptor. Nature (London) 1997; 386: 499–502.

14. Henschen A, Lottspeich F, Brantl F, Teschemacher H. Novel opioid peptides derived from casein (h-casomorphins). Hoppe-Seyler’s Z. Physiol

Chem 1979; 360:1217–1224.

15. Montecucchi PC, de Castiglione R, Piani S, Gozzini L, Erspamer V. Amino

acid composition and sequence of dermorphin, a novel opiate-like peptide

from the skin of Phyllomedusa sauvagei. Int J Peptide Protein Res 1981;


16. Erspamer V, Melchiorri P, Falconieri-Erspamer G, et al. Deltorphins: a

family of naturally occurring peptides with high affinity and selectivity for y

opioid binding sites. Proc Natl Acad Sci USA 1989; 86:5188–5192.

17. Leslie FM. Methods used for the study of opioid receptors. Pharmacol Rev

1987; 39:197–249.

18. Blume A. Interaction of ligands with the opiate receptors of brain membranes: regulation by ions and nucleotides. Proc Natl Acad Sci USA 1978;


19. Zimmerman DM, Leander JD. Selective opioid receptor agonists and

antagonists: research tools and potential therapeutic agents. J Med Chem

1990; 33:895–902.

20. Hruby VJ, Gehring CA. Recent developments in the design of receptor

specific opioid peptides. Med Res Rev 1989; 9:343–401.

21. Schiller PW. Development of receptor specific opioid peptide analogs. In:

Ellis GP, West BG, eds. Progress in Medicinal Chemistry. Vol. 28. Amsterdam: Elsevier, 1991:301–340.

22. Hruby VJ, Agnes RS. Conformation–activity relationships of opioid

peptides with selective activities at opioid receptors. Biopolymers (Peptide

Sci) 1999; 51:391–410.

23. DiMaio J, Schiller PW. A cyclic enkephalin analog with high in vitro opiate

activity. Proc Natl Acad Sci USA 1980; 77:7162–7166.

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.















DiMaio J, Nguyen TM-D, Lemieux C, Schiller PW. Synthesis and

pharmacological characterization in vitro of cyclic enkephalin analogs:

effect of conformational constraints on opiate receptor selectivity. J Med

Chem 1982; 25:1432–1438.

Berman JM, Goodman M, Nguyen TM-D, Schiller PW. Cyclic and acyclic

partial retro-inverso enkephalins: mu receptor selective enzyme resistant

analogs. Biochem Biophys Res Commun 1983; 115:864–870.

Schiller PW, Nguyen TM-D, Maziak LA, Lemieux C. A novel cyclic opioid

peptide analog showing high preference for A-receptors. Biochem Biophys

Res Commun 1985; 127:558–564.

Wilkes BC, Schiller PW. Theoretical conformational analysis of a A-selective

cyclic opioid peptide analog. Biopolymers 1987; 26:1431–1444.

Schiller PW, Weltrowska G, Nguyen TM-D, Lemieux C, Chung NN,

Marsden BJ, Wilkes BC. Conformational restriction of the phenylalanine

residue in a cyclic opioid peptide analogue: effects on receptor selectivity and

stereospecificity. J Med Chem 1991; 34:3125–3132.

Wilkes BC, Schiller PW. Molecular dynamics simulations of opioid peptide

analogs containing multiple conformational restrictions. Int J Peptide Protein Res 1992; 40:249–254.

Schiller PW, Weltrowska G, Nguyen TM-D, Lemieux C, Chung NN.

Conformational restriction of the Phe3 residue in a cyclic dermorphin

analog: effects on receptor selectivity and stereospecificity. In: Smith JA,

Rivier JE, eds. Peptides: Chemistry and Biology (Proceedings of the 12th

American Peptide Symposium). Leiden: The Netherlands: Escom Science

Publishers, 1992:97–99.

Wilkes BC, Schiller PW. Conformation–activity relationships of cyclic

dermorphin analogues. Biopolymers 1990; 29:89–95.

Yamazaki T, Ro S, Goodman M, Chung NN, Schiller PW. A topochemical approach to explain morphiceptin bioactivity. J Med Chem 1993; 36:


Cotton R, Giles MG, Miller L, Shaw JS, Timms, D. ICI 174864: a highly

selective antagonist for the opioid y-receptor. Eur J Pharmacol 1984; 97:


Corbett AD, Gillan MGC, Kosterlitz HW, McKnight AT, Paterson SJ,

Robson LE. Selectivities of opioid peptide analogues as agonists and

antagonists at the y-receptor. Br J Pharmacol 1984; 83:271–279.

Portoghese PS, Sultana M, Nagase H, Takemori AE. Application of the

message–address concept in the design of highly potent and selective nonpeptide y opioid receptor antagonists. J Med Chem 1988; 31:281–282.

Portoghese PS, Nagase H, Maloney Huss KE, Lin CE, Takemori AE. Role

of spacer and address components in peptidomimetic y opioid receptor

antagonists related to naltrindole. J Med Chem 1991; 34:1715–1720.

Schiller PW, Nguyen TM-D, Weltrowska G, Wilkes BC, Marsden BJ,

Lemieux C, Chung NN. Differential stereochemical requirements of A vs y

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.












opioid receptors for ligand binding and signal transduction: development of

a class of potent and highly y-selective peptide antagonists. Proc Natl Acad

Sci USA 1992; 89:11871–11875.

Schiller PW, Nguyen TM-D, Weltrowska G, Wilkes BC, Marsden BJ,

Schmidt R, Lemieux C, Chung NN. TIPP opioid peptides: development of

extraordinarily potent and selective y antagonists and observation of

astonishing structure–intrinsic activity relationships. In: Hodges RS, Smith

RS, eds. Peptides: Chemistry, Structure and Biology (Proceedings of the

13th American Peptide Symposium). Leiden, The Netherlands: Escom

Science Publishers, 1994:483–486.

Marsden BJ, Nguyen TM-D, Schiller PW. Spontaneous degradation via

diketopiperazine formation of peptides containing a tetrahydroisoquinoline3-carboxylic acid residue in the 2-position of the peptide sequence. Int J

Peptide Protein Res 1993; 41:313–316.

Schiller PW, Weltrowska G, Nguyen TM-D, Wilkes BC, Chung NN,

Lemieux C. TIPP[C]: a highly potent and stable pseudopeptide y opioid

receptor antagonist with extraordinary y selectivity. J Med Chem 1993;


Visconti, L.M., Standifer, K.M., Schiller, P.W., Pasternak, G.W. TIPP[C]: a

highly selective y ligand. Neurosci Lett 1994; 181:47–49.

Lee PHK, Nguyen TM-D, Chung NN, Schiller PW, Chang KJ. Tyrosineiodination converts the delta opioid peptide antagonist TIPP to an agonist.

Eur J Pharmacol 1995; 280:211–214.

Temussi PA, Salvadori S, Amodeo P, Bianchi C, Guerrini R, Tomatis R,

Lazarus LH, Picone D, Tancredi T. Selective opioid dipeptides. Biochem

Biophys Res Commun 1994; 198:933–939.

Schiller PW, Weltrowska G, Schmidt R, Berezowska I, Nguyen TM-D,

Lemieux C, Chung NN, Carpenter KA, Wilkes BC. Subtleties of structure–

agonist versus antagonist relationships of opioid peptides and peptidomimetics. J Receptor Signal Transduction Res 1999; 19:573–588.

Nevin ST, To´th G, Weltrowska G, Schiller PW, Borsodi A. Synthesis

and binding characteristics of tritiated TIPP[C], a highly specific and

stable delta opioid antagonist. Life Sci (Pharmacol Lett) 1995; 56:PL225–


Szatma´ri I, To´th G, Kerte´sz I, Schiller PW, Borsodi A. Synthesis and

binding characteristics of the tritiated TIPP analogue TICP[C], a highly

specific and stable y opioid antagonist. Peptides 1999; 20:1079–1082.

Salvadori S, Attila M, Balboni G, Bianchi C, Bryant SD, Crescenzi O,

Guerrini R, Picone D, Tancredi T, Temussi PA, Lazarus LH. y Opioidmimetic antagonists: prototypes for designing a new generation of

ultraselective opioid peptides. Mol Med 1995; 1:678–689.

Schiller PW, Schmidt R, Weltrowska G, Berezowska I., Nguyen TM-D,

Dupuis S, Chung NN, Lemieux C, Wilkes BC, Carpenter KA. Conforma-

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.












tionally constrained opioid peptide analogs with novel activity profiles. Lett

Peptide Sci 1998; 5:209–214.

Page´ D, McClory A, Mischki T, Schmidt R, Butterworth J, St-Onge S,

Labarre M, Payza K, Brown W. Novel Dmt-Tic dipeptide analogues as

selective delta-opioid receptor antagonists. Bioorg Med Chem Lett 2000;


Wilkes BC, Schiller PW. Theoretical conformational analysis of the opioid y

antagonist H-Tyr-Tic-Phe-OH and the A agonist H-Tyr-D-Tic-Phe-NH2.

Biopolymers 1994; 34:1213–1219.

Schiller PW, Nguyen TM-D, Berezowska I, Weltrowska G, Schmidt R,

Marsden BJ, Wilkes BC, Lemieux C, Chung NN. The TIPP opioid peptide

family: development of a new class of highly potent y-receptor antagonists

with extraordinary y-selectivity. In: Yanaihara N, ed. Peptide Chemistry

1992 (Proceedings of the 2nd Japanese Symposium on Peptide Chemistry.

Leiden, The Netherlands: Escom Science Publishers, 1993:337–340.

Wilkes BC, Schiller, PW. Comparative analysis of various proposed models

of the receptor-bound conformation of TIP(P)-related y opioid antagonists.

Biopolymers (Peptide Sci) 1995; 37:391–400.

Wilkes BC, Nguyen TM-D, Weltrowska G, Carpenter KA, Lemieux C,

Chung NN, Schiller PW. The receptor-bound conformation of H-Tyr-Tic(Phe-Phe)-OH related y-opioid antagonists contains all trans peptide bonds.

J Peptide Res 1998; 51:386–394.

Flippen-Anderson JL, George C, Deschamps JR, Reddy PA, Lewin AH,

Brine GA. X-ray structures of the y opioid antagonist TIPP and a protected

derivative of the y opioid antagonist ICI 174,864. Lett Peptide Sci 1994;


Wiley RA, Rich DH. Peptidomimetics derived from natural products. Med

Res Rev 1993; 13:327–384.

Abdelhamid EE, Sultana M, Portoghese PS, Takemori AE. Selective blockage

of delta opioid receptors prevents the development of morphine tolerance

and dependence in mice. J Pharmacol Exp Ther 1991; 258: 299–303.

Fundytus ME, Schiller PW, Shapiro M, Weltrowska G, Coderre TJ. The

highly selective y-opioid antagonist H-Tyr-TicC[CH2-NH]Phe-Phe-OH

(TIPP[C]) attenuates morphine tolerance and dependence. Eur J Pharmacol

1995; 286:105–108.

Zhu Y, King MA, Schuller AGP, Nitsche JF, Reidl M, Elde RP, Unterwald

E, Pasternak GW, Pintar JE. Retention of supraspinal delta-like analgesia

and loss of morphine tolerance in y opioid receptor knockout mice. Neuron

1999; 24:243–252.

Schiller PW, Weltrowska G, Schmidt R, Nguyen, TM-D, Berezowska I,

Lemieux C, Chung NN, Carpenter KA, Wilkes BC. Four different types of

opioid peptides with mixed A agonist/y antagonist properties. Analgesia

1995; 1:703–706.

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

60. Schiller PW, Fundytus ME, Merovitz L, Weltrowska G, Nguyen TM-D,

Lemieux C, Chung NN, Coderre TJ. The opioid A agonist/y antagonist DIPPNH2[c] produces a potent analgesic effect, no physical dependence and less

tolerance than morphine in rats. J Med Chem 1999; 42:3520–3526.

61. Schiller PW, Weltrowska G, Nguyen TM-D, Lemieux C, Chung NN. Novel

opioid peptide analogs with mixed A agonist/y antagonist properties. In:

Maia HLS, ed. Peptides 1994 (Proceedings of the 23rd European Peptide

Symposium) Leiden, The Netherlands: Escom Science Publishers, 1995:


62. Schmidt R, Vogel D, Mrestani-Klaus C, Brandt W, Neubert K, Chung NN,

Lemieux C, Schiller PW. Cyclic h-casomorphin analogues with mixed A

agonist/y antagonist properties: synthesis, pharmacological characterization

and conformational aspects. J Med Chem 1994; 37:1136–1144.

63. Schmidt R, Chung NN, Lemieux C, Schiller PW. Development of cyclic

casomorphin analogs with potent y antagonist and balanced mixed A

agonist/y antagonist properties. In: Kaumaya PTP, Hodges RS, eds. Peptides: Chemistry, Structure and Biology (Proceedings of the 14th American

Peptide Symposium). Leiden, The Netherlands: Escom Science Publishers,


64. Mrestani-Klaus C, Brandt W, Schmidt R, Neubert K, Schiller PW. Proton

NMR conformational analysis of cyclic h-casomorphin analogues of the

type Tyr-cyclo[-NN-D-Orn-Xaa-Gly-]. Arch Pharm Pharm Med Chem 1996;


65. Cowan A, Zhu XZ, Mosberg HI, Omnaas JR, Porreca F. Direct dependence

studies in rats with agents selective for different types of opioid receptor.

J Pharmacol Exp Ther 1988; 246:950–955.

66. Galligan JJ, Mosberg HI, Hurst R, Hruby VJ, Burks TF. Cerebral delta

opioid receptors mediate analgesia but not the intestinal motility effects of

intracerebroventricularly administered opioids. J Pharmacol Exp Ther 1984;


67. Chang KJ, Rigdon GC, Howard JL, McNutt RW. A novel, potent and

selective nonpeptidic delta opioid receptor agonist. J Pharmacol Exp Ther

1993; 267:852–857.

68. Calderon SN, Rothman RB, Porreca F, Flippen-Anderson JL, McNutt

RW, Xu H, Smith LE, Bilsky EJ, Davis P, Rice KC. Probes for narcotic

receptor mediated phenomena. 19. Synthesis of (+)-4-[(aR)-a-((2S,5R)-4allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide

(SNC80): a highly selective, nonpeptide delta opioid receptor agonist. J Med

Chem 1994; 37:2125–2128.

69. Kamei J, Saitoh A, Ohsawa M, Suzuki T, Misawa M, Nagase H, Kasuya Y.

Antinociceptive effects of the selective non-peptidic delta-opioid receptor

agonist TAN-67 in diabetic mice. Eur J Pharmacol 1995; 276:131–135.

70. Comer SD, McNutt, RW, Chang, K-J, DeCosta BR, Mosberg HI, Woods

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

JH. Discriminative stimulus effects of BW373U86: a nonpeptide ligand with

selectivity for delta opioid receptors. J Pharmacol Exp Ther 1993; 267:


71. Arakawa K, Akami T, Okamoto M, Akioka K, Nakai I, Oka T, Nagase H.

Immunosuppression by delta opioid receptor antagonist. Transplant Proc

1993; 25:738–740.

72. Hammond DL, Stapelfeld A, Drower EJ, Savage MA, Tam L, Mazur RH.

Antinociception produced by oral, subcutaneous or intrathecal administration of SC-39566, an opioid dipeptide arylalkylamide, in the rodent. J

Pharmacol Exp Ther 1994; 268:607–615.

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