P-Agonist

Table 4. Effects of p-Agonists on Growth and Carcass Composition of Growing Lambs...

Mechanism of Action. P-Agonists stimulate skeletal muscle growth by accelerating rates of fiber hypertrophy and protein synthesis, but generally do not alter muscle DNA content in parallel with the increases in protein accretion (133—135). This is in contrast to the effects of anaboHc steroids and ST on skeletal muscle growth. Both of the latter stimulate fiber hypertrophy and muscle protein synthesis, but also increase muscle DNA content coincident with increased protein accretion. Whether the P-agonists decrease muscle protein degradation is equivocal. 

The short-term or acute effects of the P-agonists may be different from chronic effects. Acute Hpolysis and glycogenolysis are not observed beyond the first day or two of treatment. Exact mechanisms of action on Hpid metaboHsm may differ among species. Chronic effects of the P-agonists reduce circulating insulin concentrations ST treatment causes an opposite change. Whereas residue levels may be of concern with adrninistration of several of the P-agonists, such is not the case for ST or GRE. 

Because of the widespread nature of adrenoceptors, nonselective P-agonists can produce many undesirable side effects. Therefore, before adrenergic agonists could become widely used in the treatment of asthma, some selectivity in action was needed. Whereas epinephrine and ephedrine have significant agonist activity at both a and P adrenoceptors, isoproterenol is a selective agonist at the P receptor (39). However, isoproterenol does not distinguish between the P and receptors and it is not active orally. 

Aerosol adniinistration of isoproterenol produces a prompt (2—5 minutes) intense bronchodilatation of relatively short (1 h) duration. The lack of P2-selectivity leads, in many cases, to tachycardia and blood pressure elevation. Also, use of isoproterenol, like all other known P-agonists, results in a down-regulation, or desensitization, of P-adrenergic receptors. This desensitization is only partial, and after time (depending on dose, patient, and agent), a stable, less responsive state is achieved in which P-agonists remain effective. Isoproterenol has been widely used for many years. 

Agonists of GPCRs a, p Agonists, histamine, 5HT2c agonists, endothelin-1, angiotensin-ll... 

Withdrawal from opioids is uncomfortable but unlikely to be fatal unless the patient has underlying medical problems. Administer the COWS to determine the severity of withdrawal. Those with a score of 5 or less require no pharmacologic intervention, while those with scores from 6 to 24 are likely to benefit from either a symptoms-based approach or the initiation of buprenorphine. Those with scores greater than 25 should receive either buprenorphine or an alternative full p agonist. 

The first known example of a mixed p agonist/5 antagonist was a TIPP analogue in which the free C-terminal carboxylate function had been replaced by a carboxamide function [37]. This compound, H-Tyr-Tic-Phe-... 

Table 3 In Vitro Opioid Activities and Receptor Affinities of Mixed p Agonist/6 Antagonists... 

The conformation of the mixed p agonist/5 antagonist H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-] in comparison to that of H-Tyr-c[-D-Orn-Phe-D-Pro-Gly-] was studied in DMSO-d6 by NMR spectroscopy and by molecular mechanics calculations [62,64]. Neither peptide showed nuclear Overhauser effects between C H protons or chemical exchange cross peaks in spectra obtained by total correlation and rotating frame Overhauser enhance-... 

The three prototype mixed p agonist/S antagonists described in this chapter have excellent potential as analgesics with low propensity to produce tolerance and dependence. The pseudotetrapeptide DIPP-NH2[ ] 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[T] 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-D-Ala-NH-(CH2)3-Ph (SC-39566), a plain p-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 p-casomorphin analogue H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-] is stabilized by intramolecular hydrogen bonds. There-... 

Wilkes BC, Schiller PW. Theoretical conformational analysis of the opioid 6 antagonist H-Tyr-Tic-Phe-OH and the p agonist H-Tyr-D-Tic-Phe-NH2. Biopolymers 1994 34 1213-1219. 

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 p agonist/ antagonist properties. Analgesia 1995 1 703-706. 

Schiller PW, Fundytus ME, Merovitz L, Weltrowska G, Nguyen TM-D, Lemieux C, Chung NN, Coderre TJ. The opioid p agonist/6 antagonist DIPP-NH2 i 1 produces a potent analgesic effect, no physical dependence and less tolerance than morphine in rats. J Med Chem 1999 42 3520-3526. 

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