P-Selective agonist

The multiple conformational restriction of dermorphin-related tet-rapeptide analogues that was performed represents a rational design of opioid peptidomimetics characterized by a high degree of structural rigid-ification. This is indicated by the fact that the p-selective agonist H-Hat-D-Orn-Aic-Glu-NH2 contains only two freely rotatable bonds, whereas there are 14 freely rotatable bonds in [Leu5]enkephalin. 

Figure 1.7. Structures of the natural adrenergic agonists, norepinephrine and epinephrine, and the synthetic p-selective agonist isoproterenol.

Amino acid substitutions have been examined in every position of dermorphin (see Ref 663 for a review). An alanine scan of the peptide indicated that substitutions in positions 4, 6, and 7 are well tolerated, whereas substitution particularly in positions 1 or 2, but also in positions 3 or 5, results in large decreases in potency in the GPI (877). A o-amino acid in position 2 is important for activity, and the L-Ala peptide is virtually inactive (<0.1% the potency of dermorphin). Tetrapeptide analogs containing D-methionine sulfoxide in position 2 are also potent p-selective agonists (878). 

Substitutions for Gly" are well tolerated, particularly in the tetrapeptide derivatives. Sarcosine (NMeGly, Sar) at position 4 in tetrapeptide derivatives enhances opioid activity in antinociceptive assays (879). Substitution of Phe in position 4 of the tetrapeptide amide yields the dermorphin/enkephalin hybrid TAPP (T -D-Ala-Phe-PheNHa) (831), which is a potent p-selective agonist (see Table 7.18). This peptide can also be considered an analog of en-domorphin-2, although TAPP was synthesized several years before the discovery of the endo-... 

McLaughlin JP, Hill KP, Jiang Q, Sebastian A, Archer S, Bidlack JM (1999) Nitrocinnamoyl and chlorocinnamoyl derivatives of dihydrocodeinone in vivo and in vitro characterization of p-selective agonist and antagonist activity. J Pharmacol Exp Ther 289 304—311... 

Which of the following is a p,-selective agonist sometimes used in acute congestive failure (A) Atenolol... 

Dobutamine is a p,-selective agonist often used in acute heart failure. The answer is (C). 

If bronchospasm is predominant, then administration by inhalation of a p -selective agonist like albuterol—or intravenous administration of theophylline—may be useful. If cardiovascular collapse is predominant, then vasopressor drugs may be helpful these include a-adrenoceptor agonists such as phenylephrine and P,-adrenoceptor agonists sueh as dobutamine or dopamine. 

H-Tyr-Gly-Gly-Phe-Met>Ala-NH2 Receptor. p-Opiate (rat brain homogenate) Activity IC50 = 28.0 nM (p selective agonist)... 

SCHEME 4.27. Practical asymmetric synthesis of estrogen receptor-P selective agonist. 

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