Phenoxybenzamine

Phenoxybenzamine [N-(2-chloroethyl)-N-(l-methyl-2-phenoxyethyi)benzylaniine] [59-96-1 ] M 303.5, m 38-40", hydrochloride [63-92-3] M 340.0, m 137.5-140", pKEtt The free base is crystd from pet ether and the HCl is crystd from EtOH/diethyl ether. 

Benzethonium chloride Benzphetamine HCI Bephenium hydroxynaphthoate Bufeniode Diazoxide Ifenprodil tartrate Phenoxybenzamine HCI Propoxyphene HCI Tiopronin T ribenoside... 

FIGURE 12.6 Measurement of full agonist affinity by the method of Furchgott. (a) Dose-response curve to oxotremorine obtained before (filled circles) and after (open circles) partial alkylation of the receptor population with controlled alkylation with phenoxybenzamine (10 jiM for 12 minutes followed by 60 minutes of wash). Real data for the curve after alkylation was compared to calculated concentrations from the fit control curve (see arrows), (b) Double reciprocal of equiactive concentrations of oxotremorine before (ordinates) and after (abscissae) alkylation according to Equation 5.12. The slope is linear with a slope of 609 and an intercept of 7.4 x 107 M-1. 

A large number of diugs interfere with the smooth muscle contraction. These compounds lower blood pressure and are referred to as antihypertensive. In this section, only those coumpounds will be mentioned that have a direct effect on smooth muscle tone. Phenylephrine is an agonist on most smooth muscles and activates ax adrenoceptors. Carbachol is an agonist on some smooth muscles and activates contraction through muscarinic receptors. Blockers of the ax-adrenoceptors such as prazosin and urapidil are competitive inhibitors of the ax-receptor in vascular and bladder smooth muscle. Phenoxybenzamine is an ineversible blocker of ax receptors and phentol-amine blocks ax and a2 receptors. Ca2+ channel blockers such as the dihydropyiidines, phenylalkyla-mines and benzothiazepines lower smooth muscle tone by blocking the L-type calcium channel. 

C2H7NO 141-43-5) see Alibendol Butethamine Ciclopirox Cloxazolam Flomoxef Haloxazolam loxitalamic acid Ketanserin Levamisole Lomustine Mabuprofen Miltefosine Nicorandil Oxetacaine Phenoxybenzamine Piperazine... 

C9H,C10 53491-30-8) see Phenoxybenzamine 7-(phenylacetamido)cephalosporanic acid sodium salt (C gH]7N2Na09S 26382-85-4) see to-Cefprozil phenylacetic acid... 

CjHjO 75-56-9) see Benproperine Cadralazine Nifurtimox Phenoxybenzamine Protheobromine Proxyphylline Secnidazole (-)-propylhexedrine... 

While the amount of noradrenaline released from the terminals can be increased by nerve stimulation, it can be increased much more by drugs, like phenoxybenzamine, which block presynaptic a-adrenoceptors. These receptors are normally activated by increased noradrenaline in the synapse and trigger a feedback cascade, mediated by... 

Noradrenergic antagonists such as phenoxybenzamine, phentolamine, and propranolol had no effect on stimulant (amphetamine) self-administration (DeWit and Wise 1977 Risner and Jones 1976 Yokel and Wise 1976). 

DeWit, H., and Wise, R.A. Blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide, but not with the noradrenergic blockers phentolamine and phenoxybenzamine. Can J Psychol 31 195-203, 1977. 

An example of an irreversible antagonist with a very long action (usually many hours) is phenoxybenzamine, which blocks a-adrenoceptors and, less potently, H,-histamine and muscarinic receptors. Its structure is shown below. Also illustrated is benzilylcholine mustard, a highly active and selective irreversible blocker of muscarinic receptors. 

FIGURE 1.23 Effect of a 10-min exposure to two concentrations of a phenoxybenzamine-like compound, dibenamine (DB), on the contractile response of a strip of rabbit aorta to adrenaline (epinephrine). (From Furchgott, R. F., Adv. Drug Res., 3, 21-55, 1966.)... 

The situation is different with a partial agonist (see Section 1.4.1). Inactivation of any of the receptors by, for example, dibenamine or phenoxybenzamine will now reduce the maximal response to the partial agonist, without the initial parallel shift in the log concentration-response curve that would be seen (e.g., Figure 1.24) with a full agonist if the tissue has a substantial receptor reserve. 

Vaupel, D. E., and Martin, W. R. (1976) Actions of methoxamine and tryptamine and their interactions with cyproheptadine and phenoxybenzamine on cat spinal cord segmental reflexes. J. Pharmacol. Exp. Ther., 196 87-96. 

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