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Bioorganic & Medicinal Chemistry May 2002A series of beta-chloroethylamines 5--18, structurally related to the irreversible alpha(1)-adrenoceptor antagonist phenoxybenzamine [PB,...
A series of beta-chloroethylamines 5--18, structurally related to the irreversible alpha(1)-adrenoceptor antagonist phenoxybenzamine [PB, N-benzyl-N-(2-chloroethyl)-N-(1-methyl-2-phenoxyethyl)amine hydrochloride, 1] and the competitive antagonist WB4101 [N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-N-[2-(2,6-dimethoxyphenoxy)ethyl]amine hydrochloride, 2], were synthesized and evaluated for their activity at alpha-adrenoceptors of the epididymal and the prostatic portion of young CD rat vas deferens. All compounds displayed irreversible antagonist activity. Most of them showed similar antagonism at both alpha(1)- and alpha(2)-adrenoceptors, whereas compounds 13 and 18, lacking substituents on both the phenoxy group and the oxyamino carbon chain, displayed a moderate alpha(1)-adrenoceptor selectivity (10--35 times), which was comparable to that of PB. Compounds 14 and 15, belonging to the benzyl series and bearing, respectively, a 2-ethoxyphenoxy and a 2-i-propoxyphenoxy moiety, were the most potent alpha(1)-adrenoceptor antagonists with an affinity value similar to that of PB (pIC(50) values of 7.17 and 7.06 versus 7.27). Interestingly, several compounds were able to distinguish two alpha(1)-adrenoceptor subtypes in the epididymal tissue, as revealed by the discontinuity of their inhibition curves. A mean ratio of 24:76 for these alpha(1)-adrenoceptors was determined from compounds 8--10, 12, and 15--17. Furthermore, compounds 9, 10, 12, 16a, and 16b showed higher affinity towards the minor population of receptors, whereas compounds 8, 15, and 17 preferentially inhibited the major population of alpha(1)-adrenoceptors. In addition, selected pharmacological experiments demonstrated the complementary antagonism of the two series of compounds and their different, preferential affinity for one of the two alpha(1)-adrenoceptor subtypes. In conclusion, we found beta-chloroethylamines that demonstrate a multiplicity of alpha(1)-adrenoceptors in the epididymal portion of young CD rat vas deferens and, as a consequence, they are possible useful tools for alpha(1)-adrenoceptor characterization.
Topics: Adrenergic alpha-Antagonists; Animals; Dioxanes; Dose-Response Relationship, Drug; Ethylamines; Inhibitory Concentration 50; Male; Phenoxybenzamine; Protein Binding; Rats; Structure-Activity Relationship; Vas Deferens
PubMed: 11886792
DOI: 10.1016/s0968-0896(01)00395-9 -
Journal of the American Veterinary... Apr 1982Phenoxybenzamine, an alpha adrenergic antagonist, was administered IV to 6 clinically normal horses, 5 horses with experimentally induced diarrhea, and 7 horses with...
Phenoxybenzamine, an alpha adrenergic antagonist, was administered IV to 6 clinically normal horses, 5 horses with experimentally induced diarrhea, and 7 horses with naturally-occurring diarrhea. It was established that a total of 2 mg of phenoxybenzamine/kg of body weight given in divided doses resulted in alpha adrenergic blockage of approximately 72 hours' duration, tranquilization, and mild constipation in the normal horse. The 5 experimental cases of diarrhea were involved in a laminitis research protocol in which laminitis was induced by oral carbohydrate overload. In all 5 of those cases, the severity of the diarrhea that accompanied the carbohydrate overload was reduced. The 7 clinical cases consisted of 2 foals and 5 adults with diarrhea, some of which were nonresponsive to conventional treatment. One of the foals did not respond to the phenoxybenzamine, and the other had a questionable response, whereas the 5 adults all responded favorably to the agent. It was concluded that phenoxybenzamine has a potential place in the therapy of some cases of diarrhea that are nonresponsive to conventional therapy. The mechanism of action of phenoxybenzamine on diarrhea is not known at this time.
Topics: Animals; Blood Pressure; Diarrhea; Female; Horse Diseases; Horses; Infusions, Parenteral; Male; Phenoxybenzamine
PubMed: 7085456
DOI: No ID Found -
Archives Internationales de... 1988To characterize the hypothermia-induced changes in the activity and kinetic constants for muscarinic receptors, we investigated the effects of hypothermia on the onset...
To characterize the hypothermia-induced changes in the activity and kinetic constants for muscarinic receptors, we investigated the effects of hypothermia on the onset and offset of action of phenoxybenzamine from the muscarinic receptors of the longitudinal muscle of the guinea-pig isolated ileum. At 37 degrees C, the onset of phenoxybenzamine action was very rapid (less than 5 min) and there was no apparent recovery of the response to ACh 70 min after washing off the phenoxybenzamine. However, the onset at 24 degrees C was very slow (30 min) and there was a complete recovery of the response to ACh 40 min after washing off the unoccluded phenoxybenzamine. We concluded that the lack of reversibility of the effects of phenoxybenzamine at 37 degrees C is due to the predominance of covalent binding between the receptors and phenoxybenzamine whereas at 24 degrees C the blockade of the muscarinic receptor by phenoxybenzamine is mainly due to simple occlusion.
Topics: Animals; Guinea Pigs; Hypothermia, Induced; Male; Phenoxybenzamine; Receptors, Muscarinic
PubMed: 3395177
DOI: No ID Found -
International Anesthesiology Clinics 2011
Topics: Adrenal Gland Neoplasms; Adrenergic alpha-Antagonists; Adult; Anesthesia; Female; Humans; Phenoxybenzamine; Pheochromocytoma; Preoperative Care; Tomography, X-Ray Computed
PubMed: 21441800
DOI: 10.1097/AIA.0b013e3181ff4db0 -
JAMA Oct 1988
Topics: Humans; Male; Phenoxybenzamine; Prostatic Hyperplasia; Urination
PubMed: 2459421
DOI: No ID Found -
Urology May 1984
Topics: Humans; Male; Phenoxybenzamine; Prostatic Hyperplasia; Urodynamics
PubMed: 6202041
DOI: 10.1016/s0090-4295(84)80020-5 -
Comprehensive Therapy Sep 1979
Topics: Dose-Response Relationship, Drug; Humans; Male; Phenoxybenzamine; Prostatic Hyperplasia
PubMed: 90580
DOI: No ID Found -
Urology Sep 1983
Topics: Humans; Male; Phenoxybenzamine; Prostatic Hyperplasia
PubMed: 6194606
DOI: 10.1016/s0090-4295(83)80036-3 -
Der Chirurg; Zeitschrift Fur Alle... May 1975
Topics: Adrenal Gland Neoplasms; Blood Pressure; Body Weight; Catecholamines; Headache; Humans; Neurologic Manifestations; Phenoxybenzamine; Pheochromocytoma; Postoperative Complications; Pulse; Vomiting
PubMed: 1149567
DOI: No ID Found -
Blood Vessels 1985The intracellular sodium content, unidirectional radiosodium efflux, and unidirectional radiosodium influx were studied in whole rat tail arteries and in rat tail artery...
The intracellular sodium content, unidirectional radiosodium efflux, and unidirectional radiosodium influx were studied in whole rat tail arteries and in rat tail artery strips. The tissues were allowed to come to a steady condition while immersed in physiological salt solution at 37 degrees C, then were subjected to a small transient mechanical disturbance or to a larger disturbance of 5-20 min duration. The small transient disturbance caused a large transient increase in the sodium content of the cells, in the radiosodium influx, and in the radiosodium efflux. The sustained disturbance caused a sustained increase in sodium content. All effects of a mechanical disturbance were prevented by blockade of alpha-adrenoreceptors with 1 microM phenoxybenzamine. Pre-treatment of the rat with reserpine was as effective as acute treatment of the artery with phenoxybenzamine in preventing the transient increase in the radiosodium efflux. It is hypothesized that mechanical disturbances cause norepinephrine release from terminal adrenergic plexuses in the artery wall, and that the binding of norepinephrine to alpha-adrenoreceptors in the smooth muscle cells causes an increase in the sodium permeability of the cell membrane.
Topics: Animals; Binding, Competitive; Ion Channels; Male; Muscle, Smooth, Vascular; Norepinephrine; Phenoxybenzamine; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Reserpine; Sodium Radioisotopes; Tail
PubMed: 2415190
DOI: 10.1159/000158604