Structure-Activity Relationship (SAR) of the Phenethylamines: A ...

Structure-Activity Relationship 

(SAR) of the Phenethylamines: 

A Focus on the Basics 

Rob Palmer 

Toxicology Associates, PLLC 

Rocky Mountain Poison & Drug Center 

University of Colorado School of Medicine 

Disclaimer 

• This is not a complete compendium of all 

substituted amphetamine derivatives and 

not all SAR twists and turns are covered 

• I hope to distill the essence of SAR studies 

into an understandable block 

• The goal is to provide some useful SAR 

tools for predicting biological activity of a 

phenethylamine molecule 

• Many references are combined for a given 

concept 

What is SAR 

• The relationship between the threedimensional 

structure of a molecule and 

its biological action. 

• What happens to the pharmacology of a 

molecule when we add to, subtract from 

or tweak its substituents and geometry 

1

Just Nine Little Carbons… 

2-Carbon 

Bridge 

Amine 

(Basic N) 

Aromatic 

Ring 

Phenethylamine Description 

• Alpha-methylphenethylamine 

• Amphetamine 

• Alpha-methylphenethylamine 

• 1-phenyl-2-aminopropane 

• Phenylisopropylamine 

Initial SAR 

β 

α 

2-Phenethylamine 

Amphetamine 

• 2-Phenethylamine largely lacks CNS 

effects with systemic administration 

• Little difference in lipophilicity between the 

two compounds 

• Both are capable of CNS penetration 

2

Initial SAR 

2-Phenethylamine 

• No α-CH 3 group 

• Lacks central effects on 

systemic administration 

• Rapidly degraded by 

MAO 

Amphetamine 

• α-methyl group yields 

amphetamine 

• Has central effects 

• Poor MAO substrate 

• Stereocenter in the 

side chain 

Basic Flavors of Amphetamines 

• Catecholamine Releasers 

• Serotonin Releasers 

• Hallucinogenic Compounds 

Stereochemistry Reminder 

• How does this work, again 

• R / S = D / L 

• Absolute Configuration 

• Determined by structure 

• d / l = + / - 

• Optical Activity 

• Experimentally determined) 

• Absolute configuration DOES NOT predict 

optical activity!!!!! 

3

Stereochemistry of the α-Carbon 

• S–(+)-amphetamine is more potent 

“amphetamine-like” enantiomer 

• More on what this means in a bit 

• There is a 4 – 10 fold stereoselective 

preference depending on assay used 

Catecholamine Releasers: 

Ring Substitution 

ortho- meta- para- 

• Rats trained to distinguish 1 mg/kg 

(+)-AMP from saline 

• ED 50 for (+)-AMP = 0.42 mg/kg 

• ED 50 for ortho-CH 3 -AMP = 4.1 mg/kg 

• meta- and para- require MUCH higher 

doses 

• Recall that ortho- is the 2-position, meta- is 

3 and para- is 4. 


N-Substitution 

R 1 R 2 Potency (%) 

H H 100 

H CH 3 200 

H CH 2 CH 3 50 

H CH 2 CH 2 CH 3 50 

CH 3 CH 3 20 

• N-Et and N-OH give nearly complete 

substitution in (+)-AMP trained rats 

• Tertiary amines are dealkylated to more 

potent secondary amines in vivo 

• Monoamine transport systems can 

accommodate either primary or N-methyl 

substituted amines 

4


Benzylic Carbon Oxidation 

S-(+)-Amphetamine Cathinone 

• Generally good retention of activity 

• ED 50 values are about equal for cathinone 

and amphetamine 

• Rats trained on saline vs (+)-AMP showed 

(+/-)-cathinone to be equipotent to (+)-AMP 

• More potent congeners have S- absolute 

configuration at the α-carbon 

• In (+)-AMP trained rats, S- is about 

double racemic potency and R- is ~30% 


Diethylpropion 

Diethylpropion 

Ethcathione 

• Diethylpropion has low monoamine 

transporter affinity 

• Prodrug for ethcathinone 

• Ethcathinone has weak 5-HT & DA activity 

• NE effects are 10 – 20 fold greater 

• Selective NE releasing agent 


Benzylic Carbon Oxidation 

Cathinone Ephedrine Norepinephrine 

• Adding a second stereocenter creates 

diastereomers 

Pseudoephedrine Ephedrine 

• R-absolute configuration has greatest 

affinity at adrenergic receptors 

5


Morpholines 

Phenmetrazine 

Phendimetrazine 

• Reduction of benzylic ketone and 

cyclization into morpholine ring 

• Phenmetrazine and phendimetrazine 

• Certainly are CNS stimulants, but 

structurally not phenethylamines 

• Not further addressed today 


Side-Chain Modification 

α-Ethylamphetamine α-Ethylmethamphetamine 

• Simple methyl to ethyl change attenuates 

amphetamine activity 

• (+)-α-Ethyl homolog of AMP does not 

produce full substitution in (+)-AMP trained 

rats 

• Racemic α-Ethyl METH homolog gives full 

substitution but had only 10% of the 

potency of AMP 


Rigid Side Chain Compounds 

Aminoindan Aminotetralin Cycloheptane 

• 2-Aminoindan (ED 50 2.1 mg/kg) fully 

substitutes for (+)-AMP (0.42 mg/kg) in rats 

• Different investigator saw only 75% of 

AMP response at triple the dose 

• Variability in tetralin reports, but is only 

about 12 – 30% potency of AMP 

• Cycloheptane derivative does not give an 

AMP-appropriate response 

6


Mechanism of Action 

• An abbreviated (possible) mechanism 

• AMP (a weak base) reduces intracellular 

pH gradient of synaptic vesicles 

• Once buffering capacity is exceeded, the 

lack of a proton gradient reduces 

transmitter uptake driving force 

• Deprotonated catecholamine may 

diffuse from vesicle along conc gradient 

• Elevated cytosolic monoamine may be 

released from cell by reversal of uptake 

pump 


SAR Summary 

Amphetamine Methamphetamine 

• Using AMP as the model, very little 

structural alteration is allowed 

• N-CH 3 (METH) increases potency ~2-fold 

• S-configuration at α-carbon is preferred 

• Assume the primary effect of interest is 

drug-induced efflux of neuronal 

catecholamines (mostly DA) 

• The optimal structure is probably AMP or 

METH without aromatic ring substituents 

Serotonin Releasers 

• Amphetamine is a relatively weak 

serotonin releaser 

p-Chloroamphetamine 

• para-Substitution dramatically increases 

neuronal serotonin release 

• para-Chloroamphetamine (PCA) is the 

classic example 

• para-Chloromethamphetamine received 

some clinical attention in the early 1970’s 

as an antidepressant 

7

Serotonin Releasers: 

PCA as a 5-HT Neurotoxin 

• PCA is a potent releaser of 5-HT from 

neuron terminals, but… 

• Small doses also cause profound and 

long-lasting central 5-HT depletion 

• Loss of 5-HT neuronal markers (e.g. 

tryptophan hydroxylase) 

• Decrease in B max for 5-HT uptake site 

• Loss of 5-HT immunoreactivity 

• Used in some animal models as a 5-HT 

neurotoxin 

• Mechanism has not been fully elucidated 


Fenfluramine and PMA 

Fenfluramine p-Methoxyamphetamine 

• Fenfluramine has some similarities to 

PCA, but may only deplete 5-HT acutely 

• p-Methoxyamphetamine (PMA) has 

significant indirect adrenergic effects 

• Also an (indirect) 5-HT releaser 

• Isomers similar in potency in releasing 

labeled 5-HT from rat brain synaptosomes 

• Legally, PMA is usually classified as an 

“hallucinogenic amphetamine” 


MDA 

MDA 

• Chemical progenitor to MDMA 

• Clinical effects of MDA described in 1959 

• Racemic MDA has effects similar to 

hallucinogenic amphetamines 

• MDA use produced a need to be with and 

talk to other people as well as a feeling of 

emotional closeness 

• In contrast to other amphetamines 

• In a dog model, MDA had both 

“amphetamine-like” and “LSD-like” effects 

• Other substituted amphetamines just 

gave “LSD-like” effects 

8


MDA – Optical Isomers 

S-(+)-MDA 

• Behavioral scoring in mice showed LSDlike 

effect of racemic MDA are due totally 

to the R-(-) isomer 

• The S-(+) isomer possesses amphetamine 

like activity 

• In cats, the S-(+) isomer produces a 

significant pressor response blocked by 

• Pretreatment with reserpine (depleted 

endogenous NE stores) 

• Pretreatment with phenoxybenzamine 

(α-adrenergic antagonist) 


MDA – Optical Isomers 

S-(+)-MDA 

• Indirect adrenergic and 5-HT releasing 

actions are stereoselective for S- 

• In synaptosomes: 

• Potent releaser of 5-HT 

• Moderately potent 5-HT uptake inhibitor 

• Very potent inhibitor of NE uptake 

• Modest effect on inhibition of DA uptake 

• 2 – 3 fold S- over R- stereoselectivity 

• S-(+)-MDA has some amphetamine-like 

activity but the primary discriminative cue 

appears to be serotonergic 



R-(-)-MDMA 

• MDMA first synthesized in 1912 

• In vitro, pharmacology is similar to MDA 

• R-MDMA has higher affinity at 5-HT 2 

• In vivo, S-MDMA is more potent 

• Discriminative cue (MDMA) is not blocked 

by ketanserin (5-HT 2 antagonist) 

• In drug discrimination studies, R-(-)-MDA 

substitutes for hallucinogenic training 

drugs, but R-(-)-MDMA does not 

• N-Methylation of MDA abolishes R- 

(hallucinogenic) activity, but has little effect 

on the S- (5-HT and catecholamine) activity 

9



MDEA 

• N-methylation has little effect on 5-HT and 

catecholamine effects 

• Range of allowable substitutions is limited 

• MDEA is similar to MDMA for 5-HT, NE 

and DA in vitro 

• DA effects of MDEA weaker than MDMA 

• N-Cyclopropyl-PCA has similar 

pharmacology to PCA 

• Probably due to N-dealkylation 

• N,N-Dialkylation leads to inactive 

compounds in vivo (N,N-Dimethyl-MDA) 

MBDB 

CAB 


Side Chain Modification 

• 2-Carbon “bridge” optimal for 5-HT release 

• Demonstrated in PCA analog studies 

• MDA and MDMA analogs with two α-CH 3 

groups are inactive in humans 

• A single α-Ethyl may be tolerated 

• MBDB & CAB (α-Ethyl MDMA & PCA) 

• Longer chains are inactive 

• An α-Et markedly attenuates DA release 

• Improves 5-HT selectivity, though still 

somewhat weaker than α-CH 3 compounds 


Aromatic Ring Substituents 

• Single substituent at 3- (e.g. CF3 in 

fenfluramine) or 4- (e.g. PCA and PMA) 

or at 3,4- (e.g. MDA, MDMA) gives potent 

5-HT releasers 

A B 

• 3-Methoxy-4-methylamphetamine (A) is a 

potent indirect-acting 5-HT releaser 

• Addition of ortho-OCH 3 (B) eliminates all 

effects on 5-HT, NE and DA transporters 

10



• Not just 5-HT uptake inhibitors 

• They also actively cause release of 

endogenous 5-HT 

• Likely involves 5-HT transporter protein 

• Indirect action with amine transporters 

(e.g. MDMA-5-HT exchange) is probably 

also involved 

• Passive diffusion into vesicles and 

transport out of the neuron by reverse 

action of the uptake pump 



• Monosubstitution at the 4-position gives 

significant 5-HT activity 

• Halogens and OCH 3 have appreciable 

catecholamine releasing actions 

• A 3-CF 3 group (e.g. fenfluramine) gives 

relatively 5-HT selective agent 

• A 3,4-dioxole disubstitution gives agents 

with 5-HT and catecholamine activity (MDA) 

• Primary amine is most potent 

• Extension of α-CH 3 to α-Et improves 5-HT 

action by attenuating catecholamine effects 

• Longer chains are not allowable 

Hallucinogens 

• Called by various names – 

psychotomimetics, hallucinogens, 

psychedelics 

• Jaffe argued that ‘psychedelic’ was the 

most appropriate moniker 

• “The feature that distinguishes the 

psychedelic agents from other classes of 

drugs is their capacity to induce states of 

altered perception, thought and feeling that 

are not experienced otherwise except in 

dreams or at times of religious exaltation.” 

11

Hallucinogenic Phenethylamines 

Mescaline 3,4,5-Trimethoxyamphetamine 

• Mescaline was the starting point of the 

substituted phenethylamine genre 

• Mescaline begat TMA in 1955 

• Nearly 200 derivatives have been 

evaluated for hallucinogenic activity 

• Shulgin’s PIHKAL is perhaps the most 

comprehensive collation of data to date 

Hallucinogenic Phenethylamines: 


• N-alkylation of hallucinogenic 

amphetamines dramatically attenuates or 

even abolishes hallucinogenic activity 

• Both receptor (5-HT 2 , 5HT 1C ) affinity and 

in vivo activity are diminished 

• N-CH 3 reduces hallucinogenic activity by 

about an order of magnitude 

• N,N-Dialkylation (even with methyl 

groups), completely abolishes 

hallucinogenic activity 

• An N-alkyl group larger than CH 3 or 

incorporation of the nitrogen into a 

heterocyclic ring leads to inactivity 


Aromatic Ring Substitution 

• 3,4,5-Trimethoxy pattern (e.g. mescaline) 

actually gives lowest potency 

hallucinogens 

• Moving 3-OCH 3 to the 2 position and/or 

replacing the 4-OCH 3 with a more 

hydrophobic group gives highly active 

hallucinogenic compounds 

• 2,4,5-trisubstituted with 2 and 5 

substituents as OCH 3 are most active 

12

Hallucinogenics based on 

2,5-Dimethoxyamphetamine 

R Trivial Name Est Dose (mg)* 

H 2,5-DMA 80 – 160 

OCH 3 TMA-2 20 – 40 

OCH 2 CH 3 MEM 20 – 50 

SCH 3 p-DOT 5 – 10 

NO 2 DON 3 – 4.5 

CH 3 DOM 3 – 10 

CH 2 CH 3 DOEt 2 – 6 

CH 2 CH 2 CH 3 DOPr 2.5 – 5 

Br DOB 1 – 3 

I DOI 1.5 – 3 

CF 3 DOTFM Animals Only 

*Data compiled from Shulgin & Shulgin (1991) 

Hallucinogenics based on 



• Are differences a result of electronics 

• Probably not – both alkyl and highly 

electronegative groups (e.g. NO 2 , CF 3 ) 

are highly active 

• Greatest activity seems to be in congeners 

with relatively hydrophobic parasubstituent 

which is fairly resistant to 

oxidative metabolism 


4-Substituent Orientation 

A B 

• 4-substituent may force 5-OCH 3 into “anti” 

orientation 

• Compound A lacks “LSD-like” activity while 

B is as potent as the flexible analog, DOB 

• H-bond donor in the receptor site that 

needs this orientation of the O lone pair 

• This orientation of the OCH 3 group is 

required to make the aromatic system 

appear electronically similar to the indole 

nucleus of 5-HT 

13



• Optimum in the 2,5-dimethoxy-4-n-alkyl 

series is the n-propyl 

• n-butyl has some activity, but n-pentyl 

does not 

• Going from n-methyl to n-octyl results in 

transition from agonist to antagonist 

• Polar 4-substituets (OH, NH 2 , CO 2 H) have 

low 5-HT 2 receptor affinities 



• 3,4,5-Trisubstituted the adjacent OCH 3 

groups push the 4-OCH 3 to lie in a plane 

nearly perpendicular to the aromatic ring 

plane 

• 4-ethoxy and 4-isopropoxy are quite potent 



• 2,5-dimethoxy series, a 4-alkoxy larger than 

OCH 3 does not increase potency or binding 

at the 5-HT 2 receptor 

• 4-Alkoxy group lies in a conformation 

allowing maximal overlap of oxygen lone 

pairs with the π-system of the aromatic ring 

• The akyl group attached to the O is forced 

to lie in the plane of the aromatic ring 

• If S rather than O, alkyl substituent is forced 

out of ring plane and compounds are potent 

14


Ring Poly-Substitutions 

• 2,4- and 2,5-dimethoxyAMP are active in 

humans (20 – 60 mg dose) 

• 3,4-DimethoxyAMP is most like 

catecholamines, but not psychoactive 

• 2,4,6-trimethoxyAMP is almost as potent as 

2,4,5-trimethoxyAMP 

• 2,3,4,5-TetramethoxyAMP was reported as 

active in humans early on, but later study 

suggests this is not the case 

DOB 

2C-B 


Side Chain Modifications 

• Removal of α-CH 3 decreases potency in 

hallucinogenic amphetamines 

• Many stay within an order of magnitude 

of α-methylated congener 

• 2C-B and 2C-I are about 1/10 the potency 

of amphetamine counterparts (DOB & DOI) 

• Hallucinogen-like activity is higher for R- 

enantiomer (in vitro and in vivo) 

• Stereoselectivity of 3 – 6 fold (NOT 

stereoespecificity) 

• The α,α-Dimethyl compounds are inactive 



• This is tricky… 

• Some in vitro receptor data but difficult 

model to reproducibly characterize in vivo 

• Probably more direct postsynaptic agonist 

activity than the other amphetamines 

• Most important receptor seems to be the 

5-HT 2 subtype 

• 5-HT 1C is probably #2 

• 5-HT 1A Hmmmmm…… 

• Tryptamines and LSD do hit 5-HT 1A 

15



• Most active seem to have: 

• Primary amino group 

• 2,5 or 3,5-dimethoxy substituents 

• Hydrophobic group at 4-position such 

as unbranched alkyl, halogen larger 

than F or alkylthio group 

• The α-CH 3 gives 2 – 10 fold greater 

potency than non-methylated congeners 

• More active enantiomer is R- (levorotatory) 

• Disubstitution at α-carbon kills activity 

• Though α-cyclopropyl has some activity 

THANKS!! 

Rob Palmer 

RPalmer@Toxicologyassoc.com 

(303) 765-3800 

16

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