References

Hieble JP, Ruffolo RR Jr. a-Adrenoceptors. In Ruffolo RR, Hollinger MA, eds. G-Protein Coupled Transmembrane Signaling Mechanisms. Boca Raton, FL CRC Press, 1995 1-34. 2. Miller SI, Ford RV, Moyer JH. Dibenzyline results of therapy in patients with hypertension and comparisons with hexamethonium, 1-hydrazinophthalazine and semipurified extracts of veratrum. N Engl J Med 1953 248 576-582. 3. Stokes GS, Marwood JF. Review of the use of alpha-adrenoceptor antagonists in hypertension. Meth Find Exp...

Rationale for P2Y2 as Target for Therapy of Lung Diseases

The initial observations that suggested a role for P2 purinoceptors in the regulation of pulmonary defense mechanisms were reported in 1991 (26). These studies focused on identification of agents that activate Cl- and water secretory pathways that might replace those that are defective in airway epithelium of cystic fibrosis (CF) patients. It was reported that ATP and UTP were equipotent in inducing active Cl- secretion when applied to the luminal surface of either normal or CF nasal epithelial...

Therapeutic Uses of Selective Muscarinic Receptor Antagonism A Nonselective Muscarinic Antagonists

Classic muscarinic receptor antagonists, such as atropine, do not distinguish between muscarinic receptor subtypes (3). Their therapeutic utility is limited by the occurrence of side effects including mydriasis, xerostomia, CNS disturbances, tachycardia, and constipation. In certain circumstances, however, the nonselective nature of these antagonists may be desirable. For example, atropine and hyoscine are used as premedication for surgical procedures in which blockade of salivary secretion,...

Unnatural bAdrenoceptor Agonists

Unnatural b-agonists interact with all or part of the epinephrine binding site and with other chemical groups in the receptor protein that are determined by the structures of the agonist and the protein. The binding site for each agonist and the nature of its active complex are, therefore, unique. These interactions involve formation of low-energy ionic and or hydrogen bonds, which contribute much to the specificity of binding, and of hydrophobic (nonpolar) binding, which...

Hypertension

Selective a1-adrenoceptor antagonists have been available as antihypertensive drugs for many years. This pharmacological class offers a number of unique and desirable therapeutic activities, particularly with respect to plasma lipoprotein profile, which is clearly favorably influenced by a1- adrenoceptor blockade (98). The roles of the individual a1-adrenoceptor subtypes in the various actions of an a1-adrenoceptor antagonist in hypertension are still largely unknown. The relative role of the...

Pharmacological Properties

Incubation of P2U-1321N1 cells with UTP resulted in a linear formation of inositol phosphates for up to 1 hr (47). This observation contrasted with previous results with P2Y2 receptors natively expressed in airway epithelial cells where desensitization, i.e., cessation of agonist effect, occurred within 5 min of drug challenge (27). The apparent lack of agonist-induced desensitization in HP2U-1321N1 was associated with the presence of a large receptor reserve. The net increase in...

The Evolution Of Highly Selective b2Adrenoceptor Agonists From Epinephrine A Why bAgonism Is a Desirable

Apart from acute bronchoconstriction that occurs during attacks of asthma, basal bronchial tone is greatly enhanced in all asthmatics. This condition is undesirable because, by impeding inspiration, it is a prime cause of the hyperresponsiveness (2) that is a cardinal feature of the disease. The cause of enhanced bronchial tone may be deduced from the response of patients to b-blockade and the attenuating action of inhaled antimuscarinic agents on it. b-Blockade causes marked...

Identifying 5HT1B1D Receptor Partial Agonists

The decision to seek a partial agonist drug candidate was pragmatic and guided by reports suggesting that 5-HT1B 1D receptors are particularly prominent in intracranial blood vessels (26,27). A more objective reason concerned the propensity of 5-HT1B 1D receptors to exhibit pharmacological synergism such that in a tissue where 5-HT1B 1D receptor activation would normally produce no effect, or a barely discernible one, the presence of a second independently acting stimulant (at threshold...

Irreversible Antagonists

The lack of subtype-selective muscarinic agonists mandates that alternative approaches be used to study the function of single muscarinic receptor subtypes in cells or tissues expressing more than one receptor. Potentially, selective receptor inactivation allows the use of a nonselective agonist of high intrinsic efficacy to stimulate one muscarinic receptor subtype in pharmacological isolation. Several P-haloakylamines, such as dibenamine (A Atdibenzyl-P-choroethylamine) and phenoxybenzamine,...

The Receptor Inactivation Method

This null method relies on comparing equal effects of the agonist before and after treatment with a receptor-inactivating agent. Such effects are considered to be due to the generation of equal stimuli, which in turn result from equal fractional receptor occupancies under the two conditions. These relationships are shown algebraically below The interaction method testing for competition. Analysis of the interaction between the partial agonist pilocarpine and the full agonist carbachol at...

Subunit Swapping

The first structural level for defining receptor-ligand interactions is to determine which subunit(s) contain the ligand-binding site. This can be achieved by adding or substituting species of subunits in a multimeric receptor complex. For example, when the a3b2 nicotinic receptor combination is expressed, nicotine is a poor agonist and neuronal bungarotoxin a very potent antagonist (33). In contrast, the a3b4 combination is very sensitive to nicotine, but relatively insensitive to neuronal...

Salbutamoland HighlySelective b2Adrenergic Bronchodilatation

Our starting objective in Glaxo Allenburys in 1963 was simply a long-acting b-adrenergic bronchodilator to replace isoprenaline, and work soon centered on Lunts' proposal (10) to make noncatechol analogs of isoprenaline since they might, like orciprenaline, be longer acting. In 1966, however, our understanding of what was achievable was transformed when AH3021, the saligenin analog of isoprenaline, was found to be hundreds of times more active on bronchial than on heart muscle and AH3365...

Muscarinic M Antagonists

Pirenzepine, an antagonist with relatively high affinity for the muscarinic Mj and modest affinity for the muscarinic M4 receptor, is approved for clinical use in the treatment of peptic ulcer disease (84). Structurally related compounds in clinical development include telenzepine (13) and nuvenzepine (85). It is arguable that a selective muscarinic M3 receptor antagonist may be useful in the treatment of peptic ulcer disease, given the role of this subtype in regulating parietal cell secretion...

Respiratory Tract

Vagal stimulation induces bronchoconstriction and mucus secretion, by activation of muscarinic receptors located on smooth muscle, vascular endothelium, submucosal cells, and neural elements 98,99 . Since cholinergic neural mechanisms may contribute to airway narrowing in asthma and chronic obstructive airway disease, muscarinic receptor antagonists are effective in treating acute bronchoconstriction, particularly that occurring in chronic obstructive airway disease 100 . Antagonists currently...