Pharmacodynamics agonists

Desensitization describes the rapid signal attenuation in response to stimulation of cells by receptor agonists. Changes in the coupling efficiency of receptors to signal transduction pathways and receptor internalization can account for desensitization and the development of pharmacodynamic tolerance. 

Schaddelee MP, Collins SD, DeJongh J, de Boer AG, Ijzerman AP, Danhof M. Pharmacokinetic/pharmacodynamic modelling of the anti-hyperalgesic and antinociceptive effect of adenosine A1 receptor partial agonists in neuropathic pain. Eur J Pharmacol 2005 May 9 514(2-3) 131-40. 

Pharmacodynamic interaction clonidine acts as an agonist at a2-receptors, and these TCAs block this receptor to varying degrees the result is an increase in blood pressure either avoid this interaction by choosing another antidepressant or increase the dose of clonidine. 

Mathot RAA, van Schaick EA, Langemeijer MWE, Soudijn W, Breimer DD, Ijzerman AP, Danhof M. Pharmacokinetic-pharmacodynamic relationship of the cardiovascular effects of the adenosine A receptor agonist A -cyclopentyladenosine (CPA) in the rat. J Pharmacol Exp Ther 1994 268 616-624. 

Walsh S.L., Geter-Douglas B., Strain E.C., Bigelow G.E. Enadoline and butorphanol evaluation of kappa-agonists on cocaine pharmacodynamics and cocaine self-administration in humans. J. Pharmacol. Exp. Ther. 299 147, 2001. 

Wienrich M, Meier D, Ensinger HA, Pharmacodynamic profile of the M-1 agonist talsaclidine in animals and man, Life Sci 22 2593-2600, 2001. 

Ephedra (ma huang) is a popular botanical incorporated into a variety of formulations for weight loss, energy or performance enhancement, and symptomatic control of asthma. A pharmacodynamic interaction leading to a fatality has been reported with concurrent use of caffeine and ephedra (62), possibly as a result of additive adrenergic agonist effect of the ephedrine alkaloids and caffeine on the cardiovascular system and the CNS (63). Ephedra was recently withdrawn from the market (64). 

AstraZeneca is developing a series of selective non-peptidic 5 opioid receptor agonists for the treatment of neuropathic pain. The compounds (e.g. cpd., 1) are in preclinical studies. In vivo, they are effective analgesics with negligible tolerance and dependence. They have parenteral and oral activity with suitable pharmacokinetics and pharmacodynamics. 

In conclusion, the investigation of peptidic and non-peptidic tool compounds for the 5 receptor have demonstrated the potential use of 5 agonists and antagonists for a variety of clinical applications, especially for the treatment of pain. Full exploitation of this potential will however only be possible with ideal non-peptidic compounds having high potency, selectivity and, above all, optimal drug metabolism and pharmacodynamic characteristics. 

Due to its high selectivity and potency at H3 receptors (/ )-a-methylhistamine (12) is nowadays used as the standard agonist in pharmacological assays related to this receptor. With regard to its pharmacodynamic properties, which were substantiated in preclinical studies [40], (R)-a-methylhistamine (12) meets all criteria of a potential drug substance. However, in contrast to its pharmacodynamic potential (ft)-a-methyl-histamine (12) suffers from its pharmacokinetic drawbacks which limit its use in both pharmacological and conceivable clinical studies. 

---