Synthesis and α-adrenoreceptor blocking properties of phenoxybenzamine-related (2-chloroethyl)-(2,3-dihydrobenzo-[1,4]dioxin-2-ylmethyl)-(2-phenoxyethyl) amines

Phenoxybenzamine and Benextramine, but Not 4-Diphenylacetoxy-N-[2-chloroethyl]piperidine Hydrochloride, Display Irreversible Noncompetitive Antagonism at G Protein-Coupled Receptors

“…Phenoxybenzamine is known to irreversibly bind to ␣-adrenergic, H 1 -histamine, and muscarinic acetylcholine (mACh) receptors (Timmermans et al, 1985;Eglen et al, 1994;Amobi and Smith, 1995;Giardinà et al, 1995Giardinà et al, , 2002Van der Graaf and Danhof, 1997;Ruffolo and Hieble, 1999;Van der Graaf and Stam, 1999;Frang et al, 2001). Benextramine has been known to irreversibly bind to ␣ 2 -adrenoceptors (Melchiorre, 1981;Belleau et al, 1982b;Lew and Angus, 1984;Hieble et al, 1985;Timmermans et al, 1985;Taouis et al, 1987;McKernan et al, 1988;Brink et al, 2000;Umland et al, 2001), 5-HT 1A -serotonergic receptors (Stanton and Beer, 1997), H 2 -histaminergic receptors (Belleau et al, 1982a), and neuropeptide Y receptors (Melchiorre et al, 1994).…”

Recent Advances in α1-Adrenoreceptor Antagonists as Pharmacological Tools and Therapeutic Agents

“…3), structurally related to the alkylating α-AR antagonist phenoxybenzamine (PB) and the competitive antagonist 32, respectively, were synthesized and evaluated for their activity at α 1 -and α 2 -ARs as irreversible antagonists [48]. They showed a marked discontinuity in their concentration-inhibition curve of α 1 -ARs of the epididymal portion of the rat vas deferens, indicating the possible existence of two α 1 -AR subtypes in the tissue.…”