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| Other names | PPA; Norephedrine; (1RS,2SR)-Phenylpropanolamine; dl-Norephedrine; (±)-Norephedrine; (1RS,2SR)-α-Methyl-β-hydroxyphenethylamine; (1RS,2SR)-β-Hydroxyamphetamine |
| AHFS/Drugs.com | Multum Consumer Information |
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| Routes of administration | By mouth |
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| Bioavailability | High[2] |
| Protein binding | 20%[3][2] |
| Metabolism | Minimal (3–4%)[3][5][2] |
| Metabolites | •Hippuric acid (~4%)[2][3] •4-Hydroxynorephedrine (≤1%)[3][2] |
| Onset of action | Oral: 15–30 minutes[2][4] |
| Eliminationhalf-life | 4 hours (range 3.7–4.9 hours)[2][4][5][6] |
| Duration of action | Oral: 3 hours[2][4] |
| Excretion | Urine: 90% (unchanged)[4][2] |
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| ECHA InfoCard | 100.035.349 |
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| Formula | C9H13NO |
| Molar mass | 151.209 g·mol−1 |
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Phenylpropanolamine (PPA), sold under many brand names, is asympathomimetic agent used as adecongestant andappetite suppressant.[7][8][9][10] It was once common inprescription andover-the-countercough and cold preparations. The medication is takenorally.[2][11]
Side effects of phenylpropanolamine include increasedheart rate andblood pressure.[12][13][14][11] Rarely, PPA has been associated withhemorrhagic stroke.[10][15][12] PPA acts as anorepinephrine releasing agent, indirectly activatingadrenergic receptors.[16][17][18] As such, it is an indirectly actingsympathomimetic.[16][17][18][9] It was once thought to act as a sympathomimetic with additional directagonist action on adrenergic receptors, but this proved wrong.[16][17][18] Chemically, phenylpropanolamine is asubstituted amphetamine and is closely related toephedrine,pseudoephedrine,amphetamine, andcathinone.[19][20][21][10] It is usually aracemic mixture of the (1R,2S)- and (1S,2R)-enantiomers ofβ-hydroxyamphetamine and is also known asdl-norephedrine.[20][7][8]
Phenylpropanolamine was firstsynthesized around 1910 and itseffects on blood pressure were characterized around 1930.[20][10] It was introduced as medicine by the 1930s.[22][10] It waswithdrawn from many markets starting in 2000 after learning that it was associated with increased risk of hemorrhagic stroke.[22][10] It was previously available bothover-the-counter and byprescription.[22][23][24][25] Phenylpropanolamine is available for both human and/orveterinary use in some countries.[23]
Phenylpropanolamine is used as adecongestant to treatnasal congestion.[12][13] It has also been used tosuppress appetite and promoteweight loss in the treatment ofobesity and has shown effectiveness for this indication.[26][27][28]
Phenylpropanolamine was previously available in theUnited Statesover-the-counter and in certaincombination drug forms byprescription.[24][25] One such example of the latter was a combination of phenylpropanolamine andchlorpheniramine, which dually contained decongestant and antihistamine effects, marketed by Tutag as 'Vernate'. These forms have all been discontinued in the U.S.,[24][25][23] although phenylpropanolamine remains available in some countries.[23]
Phenylpropanolamine producessympathomimetic effects and can causeside effects such as increasedheart rate andblood pressure.[12][13][14][11] It has been associated rarely with incidence ofhemorrhagic stroke.[22][15][12]
Certain drugs increase the chances ofdéjà vu occurring in the user, resulting in a strong sensation that an event or experience currently being experienced has already been experienced in the past. Some pharmaceutical drugs, when taken together, have also been implicated in the cause ofdéjà vu.[29] TheJournal of Clinical Neuroscience reported the case of an otherwise healthy male who started experiencing intense and recurrent sensations ofdéjà vu upon taking the drugsamantadine and phenylpropanolamine together to relieve flu symptoms.[29] He found the experience so interesting that he completed the full course of his treatment and reported it to the psychologists to write up as a case study. Because of thedopaminergic action of the drugs and previous findings from electrode stimulation of the brain,[30] it was speculated thatdéjà vu occurs as a result ofhyperdopaminergic action in themesialtemporal areas of the brain.
There has been very little research ondrug interactions with phenylpropanolamine.[2] In one study, phenylpropanolamine taken withcaffeine was found to quadruple caffeine levels.[2] In another study, phenylpropanolamine reducedtheophyllineclearance by 50%.[2]
Phenylpropanolamine acts primarily as aselectivenorepinephrine releasing agent.[18] It also acts as adopamine releasing agent with around 10-fold lowerpotency.[18] The stereoisomers of the drug have only weak or negligibleaffinity forα- andβ-adrenergic receptors.[18]
| Compound | NETooltip Norepinephrine | DATooltip Dopamine | 5-HTTooltip Serotonin | Ref |
|---|---|---|---|---|
| Dextroamphetamine (S(+)-amphetamine) | 6.6–7.2 | 5.8–24.8 | 698–1,765 | [31][32] |
| S(–)-Cathinone | 12.4 | 18.5 | 2,366 | [18] |
| Ephedrine ((–)-ephedrine) | 43.1–72.4 | 236–1,350 | >10,000 | [31] |
| (+)-Ephedrine | 218 | 2,104 | >10,000 | [31][18] |
| Dextromethamphetamine (S(+)-methamphetamine) | 12.3–13.8 | 8.5–24.5 | 736–1,292 | [31][33] |
| Levomethamphetamine (R(–)-methamphetamine) | 28.5 | 416 | 4,640 | [31] |
| (+)-Phenylpropanolamine ((+)-norephedrine) | 42.1 | 302 | >10,000 | [18] |
| (–)-Phenylpropanolamine ((–)-norephedrine) | 137 | 1,371 | >10,000 | [18] |
| Cathine ((+)-norpseudoephedrine) | 15.0 | 68.3 | >10,000 | [18] |
| (–)-Norpseudoephedrine | 30.1 | 294 | >10,000 | [18] |
| (–)-Pseudoephedrine | 4,092 | 9,125 | >10,000 | [18] |
| Pseudoephedrine ((+)-pseudoephedrine) | 224 | 1,988 | >10,000 | [18] |
| Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. Theassays were done in rat brainsynaptosomes and humanpotencies may be different. See alsoMonoamine releasing agent § Activity profiles for a larger table with more compounds.Refs:[34][16] | ||||
Phenylpropanolamine was originally thought to act as a directagonist ofadrenergic receptors and hence to act as a mixed actingsympathomimetic,[20][21] However, phenylpropanolamine was subsequently found to show only weak or negligibleaffinity for thesereceptors and has been instead characterized as exclusively an indirectly acting sympathomimetic.[9][16][17][18] It acts byinducing norepinephrine release and thereby indirectly activating adrenergic receptors.[16][17][18]
Many sympathetic hormones and neurotransmitters are based on the phenethylamine skeleton, and function generally in "fight or flight" type responses, such as increasing heart rate, blood pressure, dilating the pupils, increased energy, drying of mucous membranes, increased sweating, and a significant number of additional effects.[citation needed]
Phenylpropanolamine has relatively lowpotency as a sympathomimetic.[20] It is about 100 to 200 times less potent thanepinephrine (adrenaline) ornorepinephrine (noradrenaline) in its sympathomimetic effects, although responses are variable depending ontissue.[20]
Phenylpropanolamine is readily- andwell-absorbed withoral administration.[4][5][3]Immediate-release forms of the drug reachedpeak levels about 1.5 hours (range 1.0 to 2.3 hours) following administration.[2][5] Conversely,extended-release forms of phenylpropanolamine reach peak levels after 3.0 to 4.5 hours.[2] Thepharmacokinetics of phenylpropanolamine are linear across an oral dose range of 25 to 100 mg.[2]Steady-state levels of phenylpropanolamine are achieved within 12 hours when the drug is taken once every 4 hours.[2] There is 62%accumulation of phenylpropanolamine at steady state in terms of peak levels, whereasarea-under-the-curve levels are not increased with steady state.[2]
Thevolume of distribution of phenylpropanolamine is 3.0 to 4.5 L/kg.[2] Levels of phenylpropanolamine in thebrain are about 40% of those in theheart and 20% of those in thelungs.[4] Thehydroxyl group of phenylpropanolamine at the β carbon increases itshydrophilicity, reduces its permeation through theblood–brain barrier, and limits itscentral nervous system (CNS) effects.[4] Hence, phenylpropanolamine crosses into the brain only to some extent, has only weak CNS effects, and most of its effects are peripheral.[13][4][3][20] In any case, phenylpropanolamine can produceamphetamine-likepsychostimulant effects at very high doses.[20][4][3] Phenylpropanolamine is more lipophilic thanstructurally related sympathomimetics with hydroxyl groups on thephenyl ring likeepinephrine (adrenaline) andphenylephrine and has greater brain permeability than these agents.[3][21]
Theplasma protein binding of phenylpropanolamine is approximately 20%.[3][2] However, it has been said that no recent studies have substantiated this value.[2]
Phenylpropanolamine is not substantiallymetabolized.[5][3] It also does not undergo significantfirst-pass metabolism.[5] Only about 3 to 4% of an oral dose of phenylpropanolamine is metabolized.[3]Metabolites includehippuric acid (viaoxidativedeamination of theside chain) and4-hydroxynorephedrine (viapara-hydroxylation).[2][3][4] Themethyl group at the α carbon of phenylpropanolamine blocks metabolism bymonoamine oxidases (MAOs).[4][3][13] Phenylpropanolamine is also not asubstrate ofcatecholO-methyltransferase.[13] Thehydroxyl group at the β carbon of phenylpropanolamine also helps to increasemetabolic stability.[3]
Approximately 90% of a dose of phenylpropanolamine isexcreted in theurine unchanged within 24 hours.[2][4][5][3] About 4% of excreted material is in the form ofmetabolites.[2]
Theelimination half-life ofimmediate-release phenylpropanolamine is about 4 hours, with a range in different studies of 3.7 to 4.9 hours.[4][5][2] The half-life ofextended-release phenylpropanolamine has ranged from 4.3 to 5.8 hours.[2]
Theelimination of phenylpropanolamine is dependent on urinarypH.[2][3] At a moreacidic urinary pH, the elimination of phenylpropanolamine is accelerated and its half-life and duration are shortened, whereas at morebasic urinary pH, the elimination of phenylpropanolamine is reduced and its half-life and duration are extended.[3][2]Urinary acidifying agents likeascorbic acid andammonium chloride can increase the excretion of and thereby reduce exposure toamphetamines including phenylpropanolamine, whereasurinary alkalinizing agents includingantacids likesodium bicarbonate as well asacetazolamide can reduce the excretion of these agents and thereby increase exposure to them.[35][3][36]
Total bodyclearance of phenylpropanolamine has been reported to be 0.546 L/h/kg, while renal clearance was 0.432 L/h/kg.[2]
As phenylpropanolamine is not extensively metabolized, it would probably not be affected byhepatic impairment.[2] Conversely, there is likely to be accumulation of phenylpropanolamine withrenal impairment due to its dependence on urinary excretion.[2]
Norephedrine is a minormetabolite ofamphetamine andmethamphetamine, as shown below.[2] It is also a minor metabolite ofephedrine and a major metabolite ofcathinone.[2][4][3]
Metabolic pathways of amphetamine in humans[sources 1]  Para- Hydroxylation Para- Hydroxylation Para- Hydroxylation unidentified Beta- Hydroxylation Beta- Hydroxylation Oxidative Deamination Oxidation unidentified Glycine Conjugation  |
Phenylpropanolamine, also known as (1RS,2SR)-α-methyl-β-hydroxyphenethylamine or as (1RS,2SR)-β-hydroxyamphetamine, is asubstituted phenethylamine andamphetaminederivative.[7][19][48] It is closely related to thecathinones (β-ketoamphetamines).[19]β-Hydroxyamphetamine exists as fourstereoisomers, which included- (dextrorotatory) andl-norephedrine (levorotatory), andd- andl-norpseudoephedrine.[48][9]d-Norpseudoephedrine is also known ascathine,[7][48] and is foundnaturally inCatha edulis (khat).[49]Pharmaceutical drugpreparations of phenylpropanolamine have varied in their stereoisomer composition in different countries, which may explain differences inmisuse andside effect profiles.[9] In any case,racemicdl-norephedrine, or (1RS,2SR)-phenylpropanolamine, appears to be the most commonly used formulation of phenylpropanolamine pharmaceutically.[20][7][8]Analogues of phenylpropanolamine includeephedrine,pseudoephedrine,amphetamine,methamphetamine, andcathinone.[19]
Phenylpropanolamine, structurally, is in the substituted phenethylamine class, consisting of a cyclic benzene or phenyl group, a two carbon ethyl moiety, and a terminal nitrogen, hence the namephen-ethyl-amine.[50] The methyl group on thealpha carbon (the first carbon before the nitrogen group) also makes this compound a member of thesubstituted amphetamine class.[50]Ephedrine is theN-methyl analogue of phenylpropanolamine.
Exogenous compounds in this family are degraded too rapidly bymonoamine oxidase to be active at all but the highest doses.[50] However, the addition of the α-methyl group allows the compound to avoid metabolism and confer an effect.[50] In general,N-methylation of primary amines increases their potency, whereas β-hydroxylation decreases CNS activity, but conveys more selectivity foradrenergic receptors.[50]
Phenylpropanolamine is asmall-moleculecompound with themolecular formula C9H13NO and amolecular weight of 151.21 g/mol.[51][6] It has an experimentallog P of 0.67, while its predicted log P values range from 0.57 to 0.89.[51][6] The compound is relativelylipophilic,[3] but is also morehydrophilic than other amphetamines.[4] The lipophilicity of amphetamines is closely related to their brain permeability.[52] For comparison to phenylpropanolamine, the experimental log P ofmethamphetamine is 2.1,[53] ofamphetamine is 1.8,[54][53] ofephedrine is 1.1,[55] ofpseudoephedrine is 0.7,[56] ofphenylephrine is -0.3,[57] and ofnorepinephrine is -1.2.[58] Methamphetamine has high brain permeability,[53] whereas phenylephrine and norepinephrine areperipherally selective drugs.[59][60] The optimal log P for brain permeation and central activity is about 2.1 (range 1.5–2.7).[61]
Phenylpropanolamine has been used pharmaceutically exclusively as thehydrochloridesalt.[7][8]
Phenylpropanolamine was firstsynthesized in the early 20th century, in or around 1910.[20][10] It waspatented as amydriatic in 1913.[20] Thepressor effects of phenylpropanolamine were characterized in the late 1920s and the 1930s.[20] Phenylpropanolamine was first introduced for medical use by the 1930s.[22][10]
In the United States, phenylpropanolamine is no longer sold due to an increased risk ofhaemorrhagic stroke.[15] In a few countries inEurope, however, it is still available either by prescription or sometimes over-the-counter. InCanada, it was withdrawn from the market on 31 May 2001.[62] It was voluntarily withdrawn from the Australian market by July 2001.[63] InIndia, human use of phenylpropanolamine and its formulations was banned on 10 February 2011,[64] but the ban was overturned by the judiciary in September 2011.[65]
Phenylpropanolamine is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,BANTooltip British Approved Name, andDCFTooltip Dénomination Commune Française, whilephenylpropanolamine hydrochloride is itsUSANTooltip United States Adopted Name andBANMTooltip British Approved Name in the case of thehydrochloridesalt.[7][8][9][23] It is also known by the synonymnorephedrine.[7][8][23]
Brand names of phenylpropanolamine include Acutrim, Appedrine, Capton Diet, Control,Dexatrim, Emagrin Plus A.P., Glifentol, Kontexin,Merex, Monydrin, Mydriatine, Prolamine, Propadrine, Propagest, Recatol, Rinexin, Tinaroc, and Westrim, among many others.[7][8][23] It has also been used incombinations under brand names includingAllerest,Demazin,Dimetapp, and Sinarest, among others.[8][23]
Phenylpropanolamine is available for medical andveterinary use in some countries.[8][23]
There has been interest in phenylpropanolamine as aperformance-enhancing drug inexercise andsports.[66] However, clinical studies suggest that phenylpropanolamine is not effective in this regard.[66][4] Phenylpropanolamine is not on theWorld Anti-Doping Agency (WADA)list of prohibited substances as of 2024.[67]
In Sweden, phenylpropanolamine is still available in prescription decongestants;[68] Phenylpropanolamine is also still available in Germany. It is used in somepolypill medications like Wick DayMed capsules.
In the United Kingdom, phenylpropanolamine was available in many "all in one" cough and cold medications which usually also featureparacetamol (also known as acetaminophen) or anotheranalgesic andcaffeine and could also be purchased on its own. It is no longer approved for human use, however, and a European Category 1 Licence is required to purchase or acquire phenylpropanolamine for academic or research use.
In the United States, theFood and Drug Administration (FDA) issued a public health advisory[69] recommending against the use of the drug in November 2000. In this advisory, the FDA requested but did not require that all drug companies discontinue marketing products containing phenylpropanolamine. The agency estimates that phenylpropanolamine caused between 200 and 500 strokes per year among 18-to-49-year-old users. In 2005, the FDA removed phenylpropanolamine from over-the-counter sale and removed its "generally recognized as safe and effective" (GRASE) status.[70] Under the 2020CARES Act, it requires FDA approval before it can be marketed again, effectively banning the drug, even as a prescription.[71]
Because of its potential use inamphetamine manufacture, phenylpropanolamine is controlled by theCombat Methamphetamine Epidemic Act of 2005. However, It is still available for veterinary use in dogs as a treatment forurinary incontinence.
Internationally, an item on the agenda of the 2000Commission on Narcotic Drugs session called for including thestereoisomer norephedrine in Table I ofUnited Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.[72]
Drugs containing phenylpropanolamine were banned in India on 27 January 2011.[73] On 13 September 2011, Madras High Court revoked a ban on the manufacture and sale of pediatric drugs phenylpropanolamine andnimesulide.[74]
Phenylpropanolamine is available for use inveterinary medicine.[25] It is used to controlurinary incontinence in dogs.[75][76]
In June 2024, the USFood and Drug Administration (FDA) approved Phenylpropanolamine hydrochloride chewable tablets for the control of urinary incontinence due to a weakening of the muscles that control urination (urethral sphincter hypotonus) in dogs.[77][78][79] This is the first generic phenylpropanolamine hydrochloride chewable tablets for dogs.[77]
Urinary incontinence happens when a dog loses its ability to control when it urinates.[77] Urinary incontinence due to urethral sphincter hypotonus can happen as dogs age and as the dog’s muscle in its urethra (the tube that leads from the dog’s bladder to outside its body) weakens and loses control over its ability to hold urine.[77]
Phenylpropanolamine hydrochloride chewable tablets contain the same active ingredient (phenylpropanolamine hydrochloride) in the same concentration and dosage form as the approved brand name drug product, Proin chewable tablets, which were first approved in August 2011.[77] In addition, the FDA determined that Phenylpropanolamine hydrochloride chewable tablets contain no inactive ingredients that may significantly affect the bioavailability of the active ingredient.[77]
{{cite journal}}: CS1 maint: DOI inactive as of July 2025 (link)The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation top-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affordsp-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, fromd-amphetamine.
Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.
Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.
The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity. ... In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).
In species where aromatic hydroxylation of amphetamine is the major metabolic pathway,p-hydroxyamphetamine (POH) andp-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. ... The location of thep-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma.
The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.
The metabolism ofp-OHA top-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convertp-OHA top-OHNor after intraventricular administration.
CHEMISTRY AND STRUCTURE-ACTIVITY RELATIONSHIP OF SYMPATHOMIMETIC AMINES
β-Phenylethylamine (Table 12–1) can be viewed as the parent compound of the sympathomimetic amines, consisting of a benzene ring and an ethylamine side chain. The structure permits substitutions to be made on the aromatic ring, the α- and β-carbon atoms, and the terminal amino group to yield a variety of compounds with sympathomimetic activity. ...N-methylation increases the potency of primary amines ...
Substitution on the α-Carbon Atom
This substitution blocks oxidation by MAO, greatly prolonging the duration of action of non-catecholamines because their degradation depends largely on the action of this enzyme. The duration of action of drugs such as ephedrine or amphetamine is thus measured in hours rather than in minutes. Similarly, compounds with an α-methyl substituent persist in the nerve terminals and are more likely to release NE from storage sites. Agents such as metaraminol exhibit a greater degree of indirect sympathomimetic activity.
Substitution on the β-Carbon Atom
Substitution of a hydroxyl group on the β carbon generally decreases actions within the CNS, largely because it lowers lipid solubility. However, such substitution greatly enhances agonist activity at both α- and β- adrenergic receptors. Although ephedrine is less potent than methamphetamine as a central stimulant, it is more powerful in dilating bronchioles and increasing blood pressure and heart rate.
Metamfetamine acts in a manner similar to amfetamine, but with the addition of the methyl group to the chemical structure. It is more lipophilic (Log p value 2.07, compared with 1.76 for amfetamine),4 thereby enabling rapid and extensive transport across the blood–brain barrier.19
Lipophilicity was the first of the descriptors to be identified as important for CNS penetration. Hansch and Leo54 reasoned that highly lipophilic molecules will partitioned into the lipid interior of membranes and will be retained there. However, ClogP correlates nicely with LogBBB with increasing lipophilicity increasing brain penetration. For several classes of CNS active substances, Hansch and Leo54 found that blood-brain barrier penetration is optimal when the LogP values are in the range of 1.5-2.7, with the mean value of 2.1. An analysis of small drug-like molecules suggested that for better brain permeation46 and for good intestinal permeability55 the LogD values need to be greater than 0 and less than 3. In comparison, the mean value for ClogP for the marketed CNS drugs is 2.5, which is in good agreement with the range found by Hansch et al.22
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