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B. CONFORMATIONAL STUDY OF H-TYR-C[-ORN-2-NAL-DPRO-GLY-]

B. CONFORMATIONAL STUDY OF H-TYR-C[-ORN-2-NAL-DPRO-GLY-]

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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

4

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.



V. D AGONISTS

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

Compound



IC50

(nM)a



K yi

(nM)b



K Ai

(nM)b



K Ai /K yi



H-Tyr-Tic-NH-(CH2)2-Ph

H-Tyr-Tic-NH-(CH2)2-Ph(o-Cl)

H-Tyr-Tic-NH-CH2-CH(Ph)2

Tyr(NMe)-Tic-NH-CH2-CH(Ph)2

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

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

H-Hmt-Tic-NH-CH2-CH(Ph)2

DPDPE



82.0

8.77

3.77

0.261

1.28

8.64

0.630

5.30



5.22

1.43

0.981

0.581

0.569

3.03

2.00

16.4



69.1

96.9

28.8

12.7

886

153

1670

943



13.2

67.8

29.4

21.9

1560

50.5

835

57.5



a

b



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.



VI. CONCLUSIONS

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



j



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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.



ACKNOWLEDGMENTS

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).



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