Endogenous agonists

Endogenous cannabinoids Endogenous agonists of cannabinoid receptors... 

The pivotal role played by oxytocin and its receptor during parturition has prompted many research groups to seek an effective antagonist of these effects. The starting point for these endeavours was the endogenous agonist. 

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. 

Many of the most useful drugs are antagonists substances that reduce the action of another agent, which is often an endogenous agonist (e.g., a hormone or neurotransmitter). Though the most common mechanism is simple competition, antagonism can occur in a variety of ways. 

The identification of the morphine receptor spurred an effort in many laboratories to find an endogenous agonist for which that receptor was normally intended. Ultimately, a pair of pentapeptides that bound quite tightly to opiate receptors were isolated from mammalian brains. These peptides, called enkephalins (2, 3), show many of the activities of synthetic opiates in isolated organ systems. They do in fact show analgesic activity when injected directly into the brain. It is thought that lack of activity by other routes of administration is due to their rapid inactivation by peptide cleaving enzymes. 

NMDA receptor agonists are typically short-chain dicarboxylic amino acids such as glutamate, aspartate and NMDA. Acting at a site on the NR2 subunit, glutamate is the most potent endogenous agonist in the... 

There is evidence that y-aminobutyric acid A receptors may be modified during SE and become less responsive to endogenous agonists and antagonists. Two phases of GCSE have been identified. During phase I, each seizure produces marked increases in plasma epinephrine, norepinephrine, and steroid concentrations that may cause hypertension, tachycardia, and cardiac arrhythmias. Muscle contractions and hypoxia can cause acidosis, and hypotension, shock, rhabdomyolysis, secondary hyperkalemia, and acute tubular necrosis may ensue. 

A compound that competes with endogenous agonists for the same binding site it may be reversible or irreversible. 

A compound that, when bound, produces an effect opposite to the endogenous agonist. 

This is exemplified by the endogenous agonists of these receptors that are usually hydrophilic by nature. Adrenalin, dopamine and histamine are representative and have log D7 4 values of - 2.6, - 2.4 and - 2.9 respectively. 

As it is now clear that excitatory amino acids (EAA) play a critical role as neurotransmitters in the brain [279], in addition to the putative endogenous agonists, synthetic agonists such as NMDA 199 and (2J ,3S,4J )-a-(carboxycyclo-propyl)glycine 198 c have been identified, Eq. 79 [280]. 

Hanus L, Abu-Lafi S, Pride E, Breuer A, Vogel Z, Shalev DE, Kustanovich 1, Mechoulam R, 2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid GBl receptor, PNAS 98 3662—3665, 2001. 

Leggett JD, Aspley S, Beckett SRG, D Antona AM, Kendall DA, Kendall DA, Oleamide is a selective endogenous agonist of rat and human CBl cannabinoid receptors, Brit JPharmacol 141 253—262, 2004. 

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