Structure-Activity Relationship (SAR) of the Phenethylamines: A Focus on the Basics

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1 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

2 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

3 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

4 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. Catecholamine Releasers: N-Substitution R 1 R 2 Potency (%) H H 100 H CH 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

5 Catecholamine Releasers: 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% Catecholamine Releasers: Diethylpropion Diethylpropion Ethcathione Diethylpropion has low monoamine transporter affinity Prodrug for ethcathinone Ethcathinone has weak 5-HT & DA activity NE effects are fold greater Selective NE releasing agent Catecholamine Releasers: Benzylic Carbon Oxidation Cathinone Ephedrine Norepinephrine Adding a second stereocenter creates diastereomers Pseudoephedrine Ephedrine R-absolute configuration has greatest affinity at adrenergic receptors 5

6 Catecholamine Releasers: 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 Catecholamine Releasers: 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 Catecholamine Releasers: Rigid Side Chain Compounds Aminoindan Aminotetralin Cycloheptane 2-Aminoindan (ED 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

7 Catecholamine Releasers: 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 Catecholamine Releasers: 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

8 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 Serotonin Releasers: 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 Serotonin Releasers: 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

9 Serotonin Releasers: 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) Serotonin Releasers: 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 Serotonin Releasers: N-Substitution 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

10 Serotonin Releasers: N-Substitution 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 Serotonin Releasers: 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 Serotonin Releasers: 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

11 Serotonin Releasers: Mechanism of Action 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 Serotonin Releasers: SAR Summary 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

12 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-Substitution 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 Hallucinogenic Phenethylamines: 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

13 Hallucinogenics based on 2,5-Dimethoxyamphetamine R Trivial Name Est Dose (mg)* H 2,5-DMA OCH 3 TMA OCH 2 CH 3 MEM SCH 3 p-dot 5 10 NO 2 DON CH 3 DOM 3 10 CH 2 CH 3 DOEt 2 6 CH 2 CH 2 CH 3 DOPr Br DOB 1 3 I DOI CF 3 DOTFM Animals Only *Data compiled from Shulgin & Shulgin (1991) Hallucinogenics based on 2,5-Dimethoxyamphetamine 2,5-Dimethoxyamphetamine 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 Hallucinogenic Phenethylamines: 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

14 Hallucinogenic Phenethylamines: 4-Substituent Orientation 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 Hallucinogenic Phenethylamines: 4-Substituent Orientation 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 Hallucinogenic Phenethylamines: 4-Substituent Orientation 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

15 Hallucinogenic Phenethylamines: 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 Hallucinogenic Phenethylamines: 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 Hallucinogenic Phenethylamines: Mechanism of Action 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

16 Hallucinogenic Phenethylamines: SAR Summary 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)

Adrenergic agonists Sympathomimetic drugs. ANS Pharmacology Lecture 4 Dr. Hiwa K. Saaed College of Pharmacy/University of Sulaimani

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