4-Substituted-2,5-dimethoxyamphetamines ( DO x ) is a chemical class of substituted amphetamine derivatives featuring methoxy groups at the 2- and 5- positions of the phenyl ring , and a substituent such as alkyl or halogen at the 4- position of the phenyl ring. Most compounds of this class are potent and long-lasting psychedelic drugs , and act as highly selective 5-HT 2A , 5-HT 2B , and 5-HT 2C receptor partial agonists . A few bulkier derivatives such as DOAM have similarly high binding affinity for 5-HT 2 receptors but instead act as antagonists, and so do not produce psychedelic effects though they retain amphetamine-like stimulant effects.
23-518: The DO x family includes the following members: A number of additional compounds are known with alternative substitutions: Stimulants: Phenylethanolamine Phenylethanolamine Phenylethanolamine (sometimes abbreviated PEOH ), or β-hydroxyphenethylamine , is a trace amine with a structure similar to those of other trace phenethylamines as well as the catecholamine neurotransmitters dopamine , norepinephrine , and epinephrine . As an organic compound , phenylethanolamine
46-467: A day with an anti-inflammatory medication, they maintain open airways and prevent asthma symptoms, particularly at night. Salmeterol and formoterol are examples of these. Some examples of anticholinergics are tiotropium (Spiriva) and ipratropium bromide . Tiotropium is a long-acting, 24-hour, anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease (COPD). Only available as an inhalant, ipratropium bromide
69-485: A full hour to begin working. For this reason, it plays a secondary role in acute asthma treatment. Dry throat is the most common side effect. If the medication gets in contact with the eyes, it may cause blurred vision for a brief time. The use of anticholinergics in combination with short-acting β 2 -adrenergic agonists has been shown to reduce hospital admissions in children and adults with acute asthma exacerbations. Available in oral and injectable form, theophylline
92-566: A rapid rise in blood pressure when administered intravenously, but had little or no effect when given by any other route: doses as high as 200 mg given subcutaneously to rabbits did not alter blood pressure, nor were there any effects when the drug was intubated into the stomach. In man, a total oral dose of 1 g also produced no effects. Doses of 1–5 mg/kg, intravenously, caused no definite changes in respiration in cats or rabbits, and additional experiments showed that phenylethanolamine had no broncho-dilatory properties in animals. There
115-555: A research group at Eli Lilly . From experiments with human TAAR1 expressed in rGα s AV12-664 cells, Wainscott and co-workers observed that R-(−)-phenylethanolamine (referred to as "R-(−)-β-hydroxy-β-phenylethylamine") had an ED 50 of ~1800 nM, with an E max of ~ 110%, whereas S-(+)-phenylethanolamine (referred to as "S-(+)-β-hydroxy-β-phenylethylamine") had an ED 50 of ~1720 nM, with an E max of ~ 105%. In comparison, β-phenethylamine itself had an ED 50 of ~106 nM, with an E max of ~ 100%. In other words, phenylethanolamine
138-453: A β 2 adrenergic receptor preparation derived from transfected HEK 293 cells, Liappakis and co-workers found that in wild-type receptors, racemic phenylethanolamine had ~ 1/400 x the affinity of epinephrine, and ~ 1/7 x the affinity of norepinephrine in competition experiments with [H]- CGP-12177 . The two enantiomers of phenylethanolamine were studied for their interaction with the human trace amine associated receptor ( TAAR1 ) by
161-429: Is a TAAR1 agonist and trace amine . The pharmacokinetics of phenylethanolamine, after intravenous administration to dogs, were studied by Shannon and co-workers, who found that the drug followed the "two-compartment model", with T 1/2 (α) ≃ 6.8 mins and T 1/2 (β) ≃ 34.2 mins; the "plasma half-life" of phenylethanolamine was therefore about 30 minutes. Phenylethanolamine was found to be an excellent substrate for
184-572: Is a long-acting bronchodilator that prevents asthma episodes. It belongs to the chemical class methylxanthines (along with caffeine). It is prescribed in severe cases of asthma or those that are difficult to control. It must be taken 1–4 times daily, and doses cannot be missed. Blood tests are required to monitor therapy and to indicate when dosage adjustment is necessary. Side effects can include nausea, vomiting, diarrhea, stomach or headache, rapid or irregular heart beat, muscle cramps, nervous or jittery feelings, and hyperactivity. These symptoms may signal
207-406: Is a β-hydroxylated phenethylamine that is also structurally related to a number of synthetic drugs in the substituted phenethylamine class. In common with these compounds, phenylethanolamine has strong cardiovascular activity and, under the name Apophedrin , has been used as a drug to produce topical vasoconstriction . In appearance, phenylethanolamine is a white solid. Phenylethanolamine
230-413: Is perhaps best known in the field of bioscience as part of the enzyme name " phenylethanolamine N-methyl transferase ", referring to an enzyme which is responsible for the conversion of norepinephrine into epinephrine , as well as other related transformations. Phenylethanolamine has been found to occur naturally in several animal species, including humans. An early synthesis of phenylethanolamine
253-440: Is used in the treatment of asthma and COPD. As a short-acting anticholinergic, it improves lung function and reduces the risk of exacerbation in people with symptomatic asthma. However, it will not stop an asthma attack already in progress. Because it has no effect on asthma symptoms when used alone, it is most often paired with a short-acting β 2 -adrenergic agonist. While it is considered a relief or rescue medication, it can take
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#1733099965510276-506: The enzyme phenylethanolamine N-methyl transferase (PNMT), first isolated from monkey adrenal glands by Julius Axelrod , which transformed it into N-methylphenylethanolamine. Subsequent studies by Rafferty and co-workers showed that substrate specificity of PNMT from bovine adrenal glands for the different enantiomers of phenylethanolamine was in the order R-(−)-PEOH > R,S-(racemic)-PEOH > S-(+)-PEOH. The minimum lethal dose (m.l.d.) upon subcutaneous administration to guinea pigs
299-1515: The respiratory airway and increasing airflow to the lungs . Bronchodilators may be originating naturally within the body , or they may be medications administered for the treatment of breathing difficulties, usually in the form of inhalers . They are most useful in obstructive lung diseases , of which asthma and chronic obstructive pulmonary disease are the most common conditions. They may be useful in bronchiolitis and bronchiectasis , although this remains somewhat controversial. They are often prescribed but of unproven significance in restrictive lung diseases . Bronchodilators are either short-acting or long-acting. Short-acting medications provide quick or "rescue" relief from acute bronchoconstriction . Long-acting bronchodilators help to control and prevent symptoms. The three types of prescription bronchodilating drugs are beta-2 adrenergic agonists (short- and long-acting), anticholinergics (short- and long-acting), and theophylline (long-acting). These are quick-relief or "rescue" medications that provide quick, temporary relief from asthma symptoms or flare-ups. These medications usually take effect within 20 minutes or less, and can last from four to six hours. These inhaled medications are best for treating sudden and severe or new asthma symptoms. Taken 15 to 20 minutes ahead of time, these medications can also prevent asthma symptoms triggered by exercise or exposure to cold air. Some short-acting β-agonists, such as salbutamol , are specific to
322-850: The compound exists in the form of two enantiomers , d- and l-phenylethanolamine, or as the racemic mixture , d,l-phenylethanolamine. The dextrorotatory isomer corresponds to the S-configuration , and the levorotatory isomer to the R-configuration The data given at right is for the racemate . The synthesis of ( S )-(+)-phenylethanolamine, from (+)- mandelic acid , via (+)- mandelamide , has been described. The physical constants reported in this paper are as follows: m.p. 55–57 °C; [α] = + 47.9° (c 2.4, in ethanol). Early, classical pharmacological studies of phenylethanolamine were carried out by Tainter, who observed its effects after administering it to rabbits, cats and dogs. The drug produced
345-739: The drug increased pupil diameter, and decreased body temperature; a dose of 10 or 17.5 mg/kg decreased heart rate, but a 30 mg/kg dose caused it to increase. Other effects that were noted included profuse salivation and piloerection . Phenylethanolamine also produced behavioral effects such as stereotyped head movement, rapid eye movement, and repetitive tongue extrusion. These and other observations were suggested to be consistent with an action on α- and β-adrenergic receptors. Research by Carpéné and co-workers showed that phenylethanolamine did not significantly stimulate lipolysis in cultured adipocytes ("fat cells") from guinea pig or human. Moderate stimulation ( intrinsic activities about half that of
368-400: The hydrochloride, C 8 H 11 NO.HCl, m.p. 212 °C, and the sulfate, (C 8 H 11 NO) 2 .H 2 SO 4 , m.p. 239–240 °C. The pK a of phenylethanolamine hydrochloride, at 25 °C and at a concentration of 10mM, has been recorded as 8.90. The presence of the hydroxy-group on the benzylic carbon of the phenylethanolamine molecule creates a chiral center , so
391-507: The lack of effective β 2 -adrenergic agonists for use as bronchodilator, but are now rarely, if ever, used medically for their bronchodilatory effects. Gaseous carbon dioxide also relaxes airway musculature: hypocapnia caused by deliberate hyperventilation increases respiratory resistance while hypercapnia induced by carbon dioxide inhalation reduces it; however, this bronchodilating effect of carbon dioxide inhalation only lasts 4 to 5 minutes. Nonetheless, this observation has inspired
414-678: The lungs; they are called β 2 -adrenergic agonists and can relieve bronchospasms without unwanted cardiac side effects of nonspecific β-agonists (for example, ephedrine or epinephrine ). Patients who regularly or frequently need to take a short-acting β 2 -adrenergic agonist should consult their doctor, as such usage indicates uncontrolled asthma, and their routine medications may need adjustment. These are long-term medications taken routinely in order to control and prevent bronchoconstriction. They are not intended for fast relief. These medications may take longer to begin working, but relieve airway constriction for up to 12 hours. Commonly taken twice
437-721: The need for an adjustment in medication. It may promote acid reflux , also known as GERD, by relaxing the lower esophageal sphincter muscle. Some medications, such as seizure and ulcer medications and antibiotics containing erythromycin , can interfere with the way theophylline works. Coffee, tea, colas, cigarette-smoking, and viral illnesses can all affect the action of theophylline and change its effectiveness. A physician should monitor dosage levels to meet each patient's profile and needs. Additionally, some psychostimulant drugs that have an amphetamine like mode of action, such as amphetamine , methamphetamine , and cocaine , have bronchodilating effects and were used often for asthma due to
460-404: The reference standard, isoprenaline ) was observed in adipocytes from rat or hamster. This lipolysis was inhibited completely by bupranolol (considered to be a non-selective β-blocker ), CGP 20712A (considered to be a selective β 1 -antagonist), and ICI 118,551 (considered to be a selective β 2 -antagonist), but not by SR 59230A (considered to be a selective β 3 -antagonist). Using
483-594: Was a similar lack of effect when the drug was given subcutaneously to man. In vivo and in vitro experiments involving cat and rabbit intestinal smooth muscle showed that the drug produced relaxation and inhibition. A detailed examination of the mydriatic effect of phenylethanolamine led Tainter to conclude that this drug acted by direct stimulation of the radial dilator muscle in the eye. Shannon and co-workers confirmed and extended some of Tainter's studies. After administering phenylethanolamine to dogs intravenously, these investigators observed that 10–30 mg/kg of
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#1733099965510506-465: Was by the reduction of 2-nitro-1-phenyl-ethanol. Other early syntheses are summarized in a paper by Hartung and Munch. A more recent synthesis, providing a better yield, is by the reduction of benzoyl cyanide using LiAlH 4 . Chemically, phenyethanolamine is an aromatic compound, an amine , and an alcohol. The amino-group makes this compound a weak base , capable of reacting with acids to form salts. Two common salts of phenylethanolamine are
529-451: Was ~ 1000 mg/kg; the m.l.d. upon intravenous administration to rabbits was 25–30 mg/kg.; in rats, the m.l.d. after intravenous administration was 140 mg/kg. Stimulants: Phenylethanolamine Bronchodilator A bronchodilator or broncholytic (although the latter occasionally includes secretory inhibition as well) is a substance that dilates the bronchi and bronchioles , decreasing resistance in
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