Adrenergic derivatives

Among the indole derivatives which have found use as drugs are indo-methacin, one of the first non-steroidal anti-inflammatory agentsfll], sumatriptan, which is used in the treatment of migraine headaches[12] and pindolol[13], one of the p-adrenergic blockers. 

Synthetic Derivatives of Indoles as Pharmaceuticals. Thousands of indole derivatives have been prepared and evaluated as potential pharmaceuticals (32). Of those which have been put into use perhaps the most important are the nonsteroidal antiinflammatory agent indomethacin [53-86-1] (10) (33) and the p-adrenergic blocker pindolol [13823-86-9] (11) (34). 

A tetrahydronaphtAaleneamine derivative, 2-(5,6,7,8-tetraliydro-l-naphthaleneamiQe)-2-knidazoliQe (12), is used ia the hydrochloride form as an adrenergic agent, ie, trama2oline hydrocholoti.de, also called KB 227 and Rhinaspray. 

Neuronal Norepinephrine Depleting Agents. Reserpine (Table 6) is the most active alkaloid derived from Rauwolfia serpentina. The principal antihypertensive mechanism of action primarily results from depletion of norepinephrine from peripheral sympathetic nerves and the brain adrenergic neurons. The result is a drastic decrease in the amount of norepinephrine released from these neurons, leading to decrease in vascular tone and lowering of blood pressure. Reserpine also depletes other transmitters including epinephrine, serotonin [50-67-9] dopamine [51-61-6] ... 

Various bioisosteric replacements for a phenolic hydroxyl have been explored. One such, a lactam NH, is incorporated into the design of the 3-adrenergic blocker, carteolol O)- The fundamental synthon is carbostyril derivative K This is reacted in the usual manner with epichlorohydrin to give which is in turn reacted with t-butylamine to complete the synthesis of carteolol (3 ), a drug that appears to have relatively reduced nonspecific myocardial depressant action. Carrying this de-... 

Phthalazines commonly possess adrenergic activity. One such, carbazeran (77), is a cardiotonic agent. Its patented synthesis involves nucleophilicaromatic displacement of chiorophthal-azine derivative 7 with piperidinyl carbamate 76 to give carbazeran (77)... 

Some alicyclic 1,2-diamine derivatives have recently been shown to have interesting CNS properties. For example, eclanamine (34) is an antidepressant with a rapid onset of action. The reasons for its potency are not as yet clear but pharmacologists note that the drug desensitizes adrenergic alpha-2 receptors and antagonizes the actions of clonidine. The synthesis of eclanamine starts with attack of cyclopentene oxide (30) by dimethylamine (to give 31). This product is converted to the mesylate by reaction with sodium hydride followed by mesyl chloride. Attack of... 

A compound closely related to classical adrenergic agonists in which the para hydroxy function is however replaced by an amino group has been investigated for its activity as a growth promoter in domestic animals. Acylation of the aniline derivative 26 with chloracetyl chloride will afford acetophenone 27 the amino-ketone 28 is obtained on reaction with isopropylamine. Removal of the protecting group (29) followed by reduction of the ketone affords cimaterol (30) 5J. 

Napamezole (68) is a dihydroimidazole derivative with antidepressant activity probably as a result of its combined a 2 adrenergic receptor blockuig and serotonin uptake blocking proper ties It can be synthesized by Wittig olefination of p-tetralone (65) with diethyl (cyanomethyl) phosphonate (66) and base to give nitnle 67 Imidazoline construction on the latter was smoothly... 

An imidazole derivative which is also a hypotensive agent by virtue of adrenergic a-2-receptor blockade is imiloxan (75). Its synthe.sis begins by conversion of 2-cyanomethyl-1,4-benzodioxane (72) to its iminosMhylether with anhydrous HC in clhanol (73). Reaction of the latter with aminoacetaldehyde diethylacetal and subsequent acid treatment produces the imidazole ring (74). Alkylation of 74 with ethyl iodide mediated by sodium hydride completes the synthesis [251. 

The distinction between a- and P-adrenergic receptors was first proposed by Ahlquist in 1948 based on experiments with various catecholamine derivatives to produce excitatory (a) or inhibitory (P) responses in isolated smooth muscle systems. Initially, a further subdivision into presynaptic a2- and postsynaptic oq-receptors was proposed. However, this anatomical classification of a-adrenergic recqrtor subtypes was later abandoned. 

Derivatives of phenylethanolamine substituted by a phenolic hydroxyl on the para position have been known for some time to exhibit 0-adrenergic agonist activity. As a consequence of this property, the compounds have proven useful as bronchodilators for the treatment of asthma (see Chapter 3). Since such sympathomimetic drugs tend to have undesired activity on the cardiovascular system in addition to the desired activity on the bronchii, considerable work has been devoted to the preparation of compounds that would show selectivity for the adrenergic receptors (02> that predominate in the lung. Attachment of the side chain to a heterocyclic aromatic phenol has been one avenue that has shown promise for achieving this selectivity. 

Rhena-/3-ketoimine derivatives of several selected 2-ethylamino compounds have been prepared (36). These amines include 2-chloroethyl-amine (a DNA-alkylating reagent), cystamine ( a heparin antagonist), histamine (a potent vasodilator), tryptamine and O-methylserotonin (two indole alkaloids), and 0,0-dimethyldopamine (an adrenergic drug derivative). 

Excellent asymmetric hydrogenation of amino ketones has been applied for the syntheses of many chiral drugs. For example, the enantioselective hydrogenation of 3-aryloxy-2-oxo-l-propylamine derivatives can directly afford the l-amino-3-aryloxy-2-propanol derivatives as chiral / -adrenergic blocking agents. This has been successfully accomplished with a neutral MCCPM-Rh complex as the catalyst. With 0.01 mol.% of an (A,A)-MCCPM-Rh complex,... 

Spengler, R.N. et al., Stimulation of alpha-adrenergic receptor augments the production of macrophage-derived tumor necrosis factor, J. Immunol., 145, 1430, 1990. 

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