High Intrinsic Efficacy Research Articles

5 Centrally Acting Dopamine D2 Receptor Ligands: Agonists

The collected amount of research on D2 agonists is immense. The D2 research field has been, and still is, very dynamic. Despite this fact, only a few compounds have reached the clinic so far. At present there are clinical trials ongoing with partial D2 agonists possessing a range of intrinsic efficacies. Some of these agonists are tested for their potential effects in Parkinson's disease (high intrinsic efficacy), while others are tested for potential anti-psychotic effects (low intrinsic efficacy). An interesting possibility has arisen through the research on the synergism between D1 and D2 receptors. This could possibly be utilized in the alleviation of Parkinsonian symptomatology. The near future will show whether the compounds under evaluation hold promise for being new, valuable medicines for treating major diseases like Parkinson's disease and schizophrenia.

Anti‐plaque agents. Rationale and prospects for prevention of gingivitis and periodontal disease

Oral health surveys have shown that even in countries with established patterns of oral hygiene habits, most individuals have relatively poor gingival health. This is due to a low interest in complying with oral health procedures. A number of factors are apparent when investigating compliance to oral hygiene habits, viz only approximately 50% of the population brushes twice a day or more, brushing time is probably much too short and use of dental floss is not very prevalent. Studies of the effect of motivation on oral hygiene suggest that improvements can be achieved, but these are not maintained unless motivation is continuously reinforced. This suggests that topically applied anti-plaque agents should be used to augment mechanical plaque control. A number of product forms are available to delivery anti-plaque agents i.e., mouthrinses, dentifrices, aqueous gels, and additionally floss, chewing gum and lozenges. Any product form should provide a physically, chemically and microbiologically stable environment for the agent concerned. It should facilitate optimal bioavailability of the agents at the site of action and encourage patient compliance. Anti-plaque agents for topical administration should have the following properties: high intrinsic efficacy against a broad spectrum of oral organisms, toxicological and ecological safety, oral substantivity, no adverse reactions and good chemical stability. A number of classes of anti-plaque agents have been identified such as positively charged organic molecules, metal salts, phenols, enzymes, peroxides, sugar substitutes, fluorides and surface modifying agents. In order to achieve optimal bioavailability, the agent to be dosed should be compatible with the product form used. The 2 major product forms are rinses and dentifrices.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of pertussis toxin on α1‐adrenoceptor‐mediated vasoconstriction by the full agonist, cirazoline, and the partial agonist, (‐)‐dobutamine, in pithed rats

The role of pertussis toxin-sensitive guanine nucleotide regulatory proteins (G-proteins) in the signal transduction process(es) involved in postjunctional vascular alpha 1-adrenoceptor-mediated vasoconstriction produced by the full agonist, cirazoline, and the partial agonist, (-)-dobutamine, have been investigated in the cardiovascular system of the pithed rat. Pertussis toxin pretreatment (50 micrograms/kg, iv, 3 days prior to experimentation) only slightly inhibited the pressor response of cirazoline, and the degree of inhibition produced by pertussis toxin was roughly equivalent to the inhibition produced by the calcium channel antagonist, nifedipine (1 mg/kg, ia). In contrast, pertussis toxin pretreatment produced marked inhibition of the alpha 1-adrenoceptor-mediated pressor response to the partial agonist, (-)-dobutamine, and this large degree of inhibition was qualitatively and quantitatively similar to the degree of inhibition produced by nifedipine. The differential pattern of inhibition of full and partial alpha 1-adrenoceptor agonists by pertussis toxin suggests that the vasoconstrictor response of an alpha 1-adrenoceptor partial agonist, which is more dependent upon the translocation of extracellular calcium than a full agonist, as evidenced by its sensitivity to inhibition by nifedipine, involves a pertussis toxin-sensitive G-protein that couples the alpha 1-adrenoceptor to the calcium channel. Furthermore, for alpha 1-adrenoceptor-mediated vasoconstriction by full agonists with high intrinsic efficacy, which involves both intracellular and extracellular pools of calcium, and particularly the former, pertussis toxin only inhibits that component of the alpha 1-adrenoceptor response which is dependent upon the translocation of extracellular calcium, accounting for the limited degree of inhibition of the response to cirazoline by pertussis toxin and by nifedipine. By inference, the other component of the alpha 1-adrenoceptor-mediated pressor response to a full agonist, which is dependent upon the mobilization of intracellular stores of calcium through a process believed to involve the activation of phospholipase C, likely utilizes a pertussis toxin insensitive G-protein that is distinct from that which we propose couples the alpha 1-adrenoceptor to the calcium channel. We conclude, therefore, that the alpha 1-adrenoceptor in the vasculature of the pithed rat may be coupled to 2 distinct G-proteins, only one of which is sensitive to inhibition by pertussis toxin and links the alpha 1-adrenoceptor to the membrane calcium channel, and which may be utilized by both full agonists and partial agonists.

Interaction of Vascular Alpha-1 Adrenoceptors with Multiple Signal Transduction Pathways

In the rat vasculature, a single alpha 1-adrenoceptor may be coupled to two distinct G proteins, one of which regulates phospholipase C activity and is insensitive to pertussis toxin, and another which regulates calcium channel function and is highly sensitive to inhibition by pertussis toxin. alpha 1-Adrenoceptor agonists may in theory activate both pathways, but the efficiency of alpha 1-adrenoceptor coupling to the pertussis-toxin-insensitive pathway is low relative to the other pathway that couples the alpha 1-adrenoceptor to calcium channels. As such, only full agonists with high intrinsic efficacy can activate both pathways, whereas partial agonists, by virtue of their lower intrinsic efficacies, are less able to activate the pertussis-toxin-insensitive pathway, thereby rendering partial alpha 1-adrenoceptor agonists more sensitive than full alpha 1-adrenoceptor agonists to inhibition by calcium channel blockers and pertussis toxin.

Effects of the two partial D2 agonists (+)- and (−)-3-PPP on prolactin release in EEDQ treated male rats

The effects of pretreatment with the irreversible inactivator of brain D2 receptors N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ) on the suppression of prolactin (PRL) release induced by the two partial D2 agonist (+)- and (−)-3-(hydroxyphenyl)-N-n-propyl-piperidine [(+)-3-PPP, (−)-3-PPP] were investigated in gamma-butyrolactone (GBL) treated male rats. Pretreatment with a high dose of EEDQ (20 mg/kg, 24 h) did not influence the PRL response to (+)-3-PPP. In contrast, the effect of (−)-3-PPP was dose-dependently antagonized by EEDQ administration; thus, while pretreatment with EEDQ 2 mg/kg (24 h) failed to influence the efficacy of (−)-3-PPP, a complete antagonism of the PRL suppressive effect of the (−) enantiomer was obtained by administration of EEDQ 16 or 20 mg/kg (24 h). Moreover, in EEDQ (20 mg/kg, 24 h) treated rats (−)-3-PPP effectively antagonized the PRL inhibiting effect of the (+) enantiomer. Also, in EEDQ (20 mg/kg, 24 h) treated animals not receiving GBL (−)-3-PPP induced a dose-dependent increase in plasma levels of PRL. The data indicate that higher doses of EEDQ are required in order to reduce the responsiveness of lactotroph D2 receptors than that of various populations of brain D2 receptors. Also, the data lend support for the assumption that an altered receptor responsiveness may dramatically modify the response to a partial agonist with low intrinsic efficacy without affecting the response to a partial agonist with higher intrinsic efficacy.