Pharmacological Investigations of the
Dissociative Legal Highs’
Diphenidine,
Methoxphenidine and Analogues
J A S O N
W A L L A C H 1 ,
C O L E S T O C K 1
,
H A M I L T O N
B O R T O L O T T O 3
,
L O D G E ,
L .
,
A D A M
A D E B O Y E
H E A T H E R
G R A H A M
K A N G ,
M O R R I S 1
L .
,
Z U N E R
C O L L I N G R I D G E ,
H A L B E R S T A D T 6
A D E J A R E
T R I S T A N
,
S I M O N
D .
A .
D A V I D
B R A N D T
Introduction:What are Legal Highs?
• 1,2-Diar yl et h yl am in es represent a structural class of organic m olecules
• These com pounds com prise a wide range of pharm alogical ef f ects
• This includes anticonvulsan ts, analgesics, antidepressa nts , etc
• A num ber of these com pounds have appeared in online shops as legal highs
• Created in order to circum vent governm ent bans
Introduction:What are Legal Highs?
• These drugs produce altered states
• Ef f ects include hallucination s, euphoria, depersonali za tio ns , dissociation
• Thought to be caused by NMDAR receptor antagonism
• Overdoses and f atal interactions have occurred
• Important to study the pharmacology of these compounds
Study Area: Why?
• Legal highs are legally grey area substances
• They are m ade to im itate illegal or prescription drugs
• Most of the com pounds are novel
• The pharm acologica l ef f ects are relativel y unknown
• These com pounds are com m on on the street
Study Area: Why?
• The N -methyl -D -a sp ar ta te (NMDA) ,dopam ine (DAT), norepineph rin e (NET) and serotonin (SERT)
receptors play an im portant physiolo gic al role
• This includes breathing, locom otion, m em ory, m ood, m em ory, appetite, etc.
• These novel com pounds m ay produce prof ound pharm alogical ef f ects
• Theref ore, having relevant m edical uses in the f uture
• Or prof ound uses on the user’s health
Methods
• In vitro binding af f inities (Ki) of the target com pounds at the PCP site within the NMDAR channel
• Radioligands and concentrati ons used f or additional 45 CNS receptor binding assays are listed as
supporting inf orm ation
• Monoam ine reuptake inhibition assays were perf orm ed via the NIMH PDSP as previousl y described
• In Vitro Field Excitator y Postsyna pti c Potential ( f EPSP ) Experim ents were perf orm ed
• In Vivo Pre -pulse Inhibition (PPI) Experim ents were perf orm ed
• Also, acoustic startle apparatus and test sessions
Methods
Methods
Results
• All the target com pounds displaye d lower af f inities at all other CNS sites evaluated relative to
NMDAR with the exception of 4 -MXP
• The startle response is attenuated if the startle -ind uci ng stim ulus is preceded by a weak
subthreshold prepulse
• In all cases, the NMDAR -f EPSP declined slowly in the presence of both the DPH analogues and
the established channel blocking NMDAR antagonists
• Such slow in vitro kinetics are m ore rem iniscent of MK -801 than of ketam ine
• Five 1,2 -diar yle th ylam i nes including the ‘legal highs’ DPH and 2 -MXP, were f ound to be relativel y
selective NMDAR antagonists.
Results
• Place Relevant Graphs here
Results
• Place Relevant Graphs here
Discussion
• Taken together, the presented results are consistent with the dissociative ef f ects of these
com pounds anecdotall y reported by hum an users. These results hold signif icance f or potential
therapeutic use, governm ental regulation and harm reduction strategies
• The study seem ed well perf orm ed
Discussion
• Taken together, the presented results are consistent with the dissociative ef f ects of these
com pounds anecdotall y reported by hum an users. These results hold signif icance f or potential
therapeutic use, governm ental regulation and harm reduction strategies
• The study seem ed well perf orm ed
References