Structural Modification of the Designer Stimulant α-Pyrrolidinovalerophenone (α-PVP) Influences Potency at Dopamine Transporters

Article abstract of DOI:10.1021/acschemneuro.5b00160

α-Pyrrolidinovalerophenone (α-PVP, 7) is an illegal synthetic stimulant that is being sold on the clandestine market as flakka and gravel. The potent pharmacological effects of α-PVP are presumably mediated by inhibition of dopamine uptake at the dopamine transporter (DAT). However, little is known about how structural modification of α-PVP influences activity at DAT. Eleven analogs of α-PVP were synthesized and examined for their ability to inhibit uptake of [³H]dopamine and [³H]serotonin in rat brain synaptosomes. None of the analogs significantly inhibited [³H]serotonin uptake when tested at 10 μM at the serotonin transporter (SERT). All of the analogs behaved as DAT reuptake inhibitors, but potencies varied over a >1500-fold range. Potency was primarily associated with the nature of the α-substituent, with the more bulky substituents imparting the highest potency. Expansion of the pyrrolidine ring to a piperidine reduced potency up to 10-fold, whereas conformational constraint in the form of an aminotetralone resulted in the least potent compound. Our study provides the first systematic and comparative structure-activity investigation on the ability of α-PVP analogs to act as inhibitors of DAT.

Full text of DOI:10.1021/acschemneuro.5b00160

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Structural modification of the designer stimulant α-
pyrrolidinovalerophenone (α-PVP) influences potency at dopamine
transporters
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R. Kolanos1, F. Sakloth1, A. D. Jain1, J S Partilla2, M H Baumann2, R. A Glennon1
1Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth
University, 800 East Leigh Street, PO Box 980540, Richmond, VA 23298, USA
2Designer Drug Research Unit, Intramural Research Program, National Institute on Drug
Abuse, National Institutes of Health, Baltimore, MD 21224, USA
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ABSTRACT
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αꢀPyrrolidinovalerophenone (αꢀPVP; 7) is an illegal synthetic stimulant that is being sold
on the clandestine market as “flakka” and “gravel”. The potent pharmacological effects
of αꢀPVP are presumably mediated by inhibition of dopamine uptake at the dopamine
transporter (DAT). However, little is known about how structural modification of αꢀPVP
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influences activity at DAT. Eleven analogs of αꢀPVP were synthesized and examined for
their ability to inhibit uptake of [3H]dopamine and [3H]serotonin in rat brain
synaptosomes. None of the analogs significantly inhibited [3H]5ꢀHT uptake when tested
at 10 ꢁM at the serotonin transporter (SERT). All of the analogs behaved as DAT
reuptake inhibitors, but potencies varied over a >1,500ꢀfold range. Potency was
primarily associated with the nature of the αꢀsubstituent, with the more bulky
substituents imparting the highest potency. Expansion of the pyrrolidine ring to a
piperidine reduced potency up to 10ꢀfold, whereas conformational constraint in the form
of an aminotetralone resulted in the least potent compound. Our study provides the first
systematic and comparative structureꢀactivity investigation on the ability of αꢀPVP
analogs to act as inhibitors of DAT.
KEYWORDS:
Synthetic cathinones, αꢀPVP, flakka, αꢀPPP, αꢀPBP, dopamine transporter, serotonin
transporter, DAT, SERT
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INTRODUCTION
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Various classes of soꢀcalled “designer drugs” have appeared on the clandestine market
in recent years,1,2 and the 18ꢀmonth period from July 1, 2012 to January 1, 2014
witnessed the identification of 97 new psychoactive substances (NPS) as reported by
the United Nations Office of Drugs and Crime.3 One class of NPS is the “synthetic
cathinones”;1 these agents are analogs of the naturallyꢀoccurring substance cathinone
(1), or the synthetic agent methcathinone (2),1,3 and are substituted aminophenones
typified by the general chemical scaffold 3. Cathinone (1) and methcathinone (2), as
well as amphetamine (4) and methamphetamine (5), act primarily as releasing agents at
the dopamine transporter (DAT) (reviewed4). Some synthetic cathinone analogs,
depending upon their specific pendant substituents, also are capable of releasing other
neurotransmitters such as serotonin (5ꢀHT) via the 5ꢀHT transporter (SERT) or
norepinephrine from the norepinephrine transporter (NET).4ꢀ6 One of the first synthetic
cathinone analogs identified in psychoactive “bath salts” products in the United States
was 3,4ꢀmethylenedioxypyrovalerone (MDPV; 6).7 MDPV (6) is structurally distinct
compared to other synthetic cathinones because it contains a pyrrolidine ring, rather
than a primary amine or Nꢀmethyl amine, and an extended αꢀcarbon side chain, rather
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than an αꢀmethyl group. Related to its structural peculiarities, MDPV (6) was identified
as the first clandestine synthetic cathinone analog to act at DAT as a dopamine
reuptake inhibitor rather than as a releasing agent.7ꢀ12 The acute effect of DAT
releasing agents (i.e., substrates) and DAT inhibitors is essentially the same: increased
synaptic concentrations of dopamine. Hence, whereas cathinone (1) and methcathinone
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(2) act analogous to amphetamine (4) and methamphetamine (5), MDPV (6) behaves
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more akin to cocaine.3,4
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Previously, we investigated some of the structureꢀactivity relationships (SAR) for MDPV
(6) and found that a tertiary amine and an extended αꢀcarbon side chain are optimal for
these agents to act as inhibitors of DAT, with the proviso that one of these two structural
elements be present.13
NHꢀR
CH3
NHꢀR
CH3
NR1R2
R
O
O
4 R = ꢀH
5 R = ꢀCH3
1 R = ꢀH
2 R = ꢀCH3
3
N
N
O
O
CH3
CH3
O
O
6
7
The presence of the MDPV (6) methylenedioxy group has little impact on DAT
transporter action; that is, αꢀPVP (7) is a potent DAT reuptake inhibitor similar in
potency to MDPV.8,14 Consistent with this action, αꢀPVP (7) produces locomotor
stimulation in rats14,15 and mice16 and, in rats, αꢀPVP is selfꢀadministered,14 reduces
ICSS thresholds,17 and substitutes for methamphetamine in tests of stimulus
generalization.18 Taken together, preclinical data indicate that αꢀPVP (7) has a high risk
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for abuse in human users, and the agent has appeared on the clandestine market (i.e.,
as flakka or gravel) and was classified as a U.S. Schedule I substance in March of
2014.19
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As part of a continuing SAR study on the interaction of synthetic cathinones with DAT,
the present investigation focused on a) the role of the αꢀPVP (7) side chain (i.e., length,
bulk), b) the impact of expansion of the pyrrolidine moiety of αꢀPVP to a piperidine ring,
and c) the influence of conformational constraint of the side chain. The purpose of our
study was to determine the role of structural modifications of cathinones on DAT action,
and to provide a greater understanding of agents that have been, or might be,
scheduled as controlled substances. Even though αꢀPVP lacks action at the serotonin
transporter,14 the effect of the above structural modifications have not been examined;
hence, the actions of these agents at SERT was also investigated.
RESULTS
αꢀPVP (7), as its hydrochloride salt, was prepared as previously reported20 and was
available from an earlier study.13 Compounds 1121,22 and 1523 were prepared as
hydrochloride salts according to literature procedures. In general, the other compounds
were prepared from their corresponding αꢀbromophenones by reaction with pyrrolidine
or piperidine. For example, 8 was prepared from bromophenone 18, 12 from 19, 13
from 21, 14 from 22, and 16 from 23. Compound 17 was prepared in a similar manner
from 2ꢀbromoꢀ3,4ꢀdihydronaphthalenꢀ1(2H)ꢀone and pyrrolidine.
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Removal of the side chain of 7 (i.e., replacement of the αꢀnꢀpropyl substituent by ꢀH)
affords the simplest possible aminophenone, 8; compound 8 (IC50 = 3,250 nM; Table 1
and Figure 1) was 185ꢀfold less potent than 7 (IC50 = 17.5 nM). The αꢀmethyl analog 9
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(IC50 = 196.7 nM) displayed improved potency as did its αꢀethyl homolog 10 (IC50 = 63.3
nM). The branched isopropyl analog 11 (IC50 = 92.3 nM) displayed potency similar to
10. Although the potency of the latter compounds was enhanced relative to 8, none was
as potent as 7. Further homologation to the nꢀbutyl compound (12; IC50 = 11.6 nM)
resulted in a small increase in potency. The αꢀcyclopentyl analog was as potent as 7
(13; IC50 = 17.1 nM) whereas the potency of the corresponding cyclohexyl analog (14;
IC50 = 8.3) was about twice that.
Expansion of the pyrrolidine moiety to a piperidine ring resulted in decreased potency.
Compounds 15 (IC50 = 2,490 nM) and 16 (IC50 = 128 nM; Table 1 and Figure 1), the
piperidine counterparts of 9 and 7, respectively, displayed reduced potency by as much
as 10ꢀfold. Conformational constraint of 10 as a tetralone (i.e., 17; IC50 = 12,900 nM)
decreased potency by 200ꢀfold.
A cursory inspection of the data for pyrrolidine compounds 7ꢀ14 intimated a possible
relationship between potency and substituent “size”. Hansch analysis of the potencies
(pIC50 values for inhibition of DAT) of these eight compounds revealed correlations both
with the volume (Vol) of their αꢀsubstituent (r = 0.909) as well as with their lipophilic
character (π) (r = 0.917) (Figure 2). However, for the substituents in this set, Vol and π
were highly interꢀcorrelated (r = 0.997, p < 0.0001).
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Table 1. Potency of αꢀPVP (7) analogs as inhibitors at DAT.a
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N
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O
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15, 16
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7 ꢀ 14
R
IC50, nM (SD)
3,250 (±418)
8
ꢀH
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ꢀCH3
196.7
b
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ꢀCH2CH3
63.3
ꢀCH2CH2CH3
ꢀCH(CH3)2
ꢀCH2(CH2)2CH3
ꢀC5H9
17.5 (±1.7)
92.3 (±11.6)
11.6 (±0.6)
17.1 (±2.5)
8.3 (±1.1)
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ꢀC6H11
ꢀCH3
2,490 (±241)
128 (±13)
ꢀCH2CH2CH3
ꢀꢀꢀ
12,900 (±1,890)
a Compounds had no activity at SERT at 10,000 nM.
b Data reported earlier.14
None of the analogs significantly inhibited [3H]5ꢀHT uptake at SERT when tested at 10
ꢁM.
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Figure 1. Inhibition of [3H]dopamine uptake by αꢀPVP analogs. The upper panel depicts
effects of altering αꢀcarbon chain length (8, 11, 12), whereas the lower panel depicts
effects of ring expansion (15, 16) or conformational constraint (17). Data are mean ±
SD for n=3 experiments performed in triplicate. Uptake inhibition curves were generated
by incubating rat caudate synaptosomes with compounds diluted in assay buffer as
described in Methods.
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Figure 2.
Relationship between pIC50 for inhibition of DAT versus substituent
volume in Å3 (upper panel; r = 0.909, p = 0.0017) and lipophilicity (π) (lower panel; r =
0.917, p = 0.0013) for compounds 7ꢀ14.
DISCUSSION
It is now appreciated that the length of the αꢀcarbon side chain of MDPV (6) plays a role
in its ability to inhibit the reuptake of dopamine.13,14 However, the precise role of various
side chain features (i.e., length, bulk) has not been previously examined in a systematic
fashion. In the present investigation, we used αꢀPVP (7), the structural parent of MDPV
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(6), as our reference compound. The side chain of αꢀPVP (7) was truncated from an nꢀ
propyl to an ethyl (i.e., 10), to a methyl group (i.e., 9), or eliminated altogether (i.e., 8).
All three compounds displayed reduced potencies. Each of these compounds behaved
as reuptake inhibitors at DAT, but with potencies varying over a 185ꢀfold range.
Homologation of the αꢀnꢀpropyl substituent of αꢀPVP (7) to an nꢀbutyl group (i.e., 12)
resulted in retention of potency. Branching was tolerated (comparing 11 with 10), and
branching, using somewhat larger substituents (comparing 13 with 7 or 12), was also
tolerated or resulted in increased potency (i.e. 14).
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For eight of the examined pyrrolidine analogs (7ꢀ14), there was a significant correlation
between potency and both αꢀsubstituent volume (Vol) and lipophilicity (π). However, due
to an interꢀcorrelation between the Vol and π parameters (for the substituents that were
used), additional compounds will need to be examined to determine which of the two
properties is more important.
Two pairs of compounds were examined where the pyrrolidine ring was expanded to a
piperidine ring (i.e., compare 15 with 9, 16 with 7); in both cases, potency was
decreased. The conformationallyꢀconstrained compound 17, although retaining action
as a reuptake inhibitor, was only very weakly active.
To date, there has been only one investigation that examined the ability of
pyrrolovalerophenones to act as inhibitors of DAT22 and the few comparisons that can
be made involve its 3,4ꢀdichloro derivative (i.e., 3,4ꢀdichloroꢀαꢀPVP). The results of the
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present investigation are generally consistent with what was previously found, although
direct comparisons should be made with caution since ring substituents in the prior
study might influence the overall actions of the compounds. With respect to 3,4ꢀ
dichloroꢀαꢀPVP: a) shortening the length of the side chain from an nꢀpropyl to an ethyl
group (IC50 = 43 nM and 55 nM, respectively) had little effect on potency as DAT
reuptake inhibitors, b) ring expansion of the pyrrolidine to a piperidine moiety (IC50 =
666 nM) decreased potency by about 15ꢀfold, and c) the compounds were more
effective as inhibitors of DAT than of SERT.22
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Overall, and in agreement with an earlier suggestion,13 an extended αꢀsubstituent is not
a structural requirement for synthetic cathinones to behave as DAT inhibitors when a
tertiary amine is present. For the pyrrolovalerone analogs examined here, it is evident
that the length, volume, and/or lipophilicity of the αꢀsubstituent governs the potency of
these tertiary amines in the absence of any other structural modifications. Expansion of
the pyrrolidine to a piperidine ring, and conformational constraint of the side chain,
resulted in reduced potency. Several of the compounds characterized here, including αꢀ
PVP (7), αꢀpyrrolidinopropiophenone (αꢀPPP, 9), and αꢀpyrrolidinobutyrophenone (αꢀ
PBP,10) have been found on the clandestine market in recent times.1 Given the
predicted proliferation of stimulant NPS in the future, our findings should provide
guidance as to which new agents might pose risks to public health and should be
considered for future scheduling.
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METHODS
Chemistry
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All commercially available reagents and solvents were purchased from SigmaꢀAldrich
Co. (St. Louis, MO) and Platte Valley Scientific Product List (Gothenburg, NE), and
used as delivered. Melting points were measured in glass capillary tubes (Thomasꢀ
Hoover melting point apparatus) and are uncorrected. 1H NMR spectra were recorded
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with a Bruker 400 MHz spectrometer. Chemical shifts (δ) are reported in parts per
million (ppm) relative to tetramethylsilane as internal standard. Reactions and product
mixtures were routinely monitored by thinꢀlayer chromatography (TLC) on silica gel
precoated F254 Merck plates.
2-(1-Pyrolidinyl)-1-acetophenone Oxalate (8). This compound has been previously
reported as its HCl salt24 but difficulty in crystallizing the material led us to prepare an
oxalate salt. Pyrrolidine (0.84 mL, 10.04 mmol) was added to a stirred solution of 2ꢀ
bromoacetophenone (18) (2 g, 10.04 mmol) and NEt3 (1.02 mL, 10.04) in anhydrous
benzene (15 mL) under an N2 atmosphere at room temperature. The reaction mixture
was allowed to stir at room temperature for 24 h, and was filtered and the solvent
evaporated under reduced pressure to yield 1.82 g (96%) of the crude free base of
which 1.00 g was dissolved in anhydrous Et2O (10 mL) and cooled to 0 °C. Oxalic
acid/Et2O (15 mL) was added and the mixture was allowed to stir at room temperature
for 48 h. The precipitate was collected by filtration to yield a solid that was recrystallized
from anhydrous MeOH to afford 0.35 g (24%) of the target compound as brown crystals:
mp 218ꢀ220 °C; 1H NMR (DMSOꢀd6) δ 1.95 (s, 4H, CH2), 3.23 (m, 2H CH2), 4.92 (s, 2H,
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CH2), 7.59 (s, 2H, ArH) 7.72 (s, 1H, ArH), 7.98 (s, 2H, ArH); Anal. Calcd for
(C12H15NO—C2H2O4) C, 60.21; H, 6.14; N, 5.02. Found: C, 59.97; H, 6.19; N, 5.00.
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1-Phenyl-2-(pyrrolidin-1-yl)hexanone Oxalate (12). This compound has been
previously reported as its HCl salt25 but difficulty in crystalizing the material led us to
prepare an oxalate salt. Pyrrolidine (3 mL) was added at 0 °C (iceꢀbath) to 2ꢀbromoꢀ1ꢀ
phenylhexanone26 (19) (1.00 g, 4 mmol) under an N2 atmosphere. The reaction mixture
was allowed to stir at room temperature for 22 h, quenched by the addition of H2O (25
mL), and extracted with EtOAc (3 x 15 mL). The combined organic portion was washed
with H2O (4 x 25 mL), brine (20 mL), dried (Na2SO4), and evaporated under reduced
pressure to yield the free base which was converted into an oxalate salt using oxalic
acid/Et2O to give a crude solid that upon recrystallization from iꢀPrOH afforded 0.26 g
(19%) of 12 as buffꢀcolored crystals: mp 129–131 °C; 1H NMR (DMSOꢀd6) δ 0.76 (t, 3H,
CH3), 1.18ꢀ1.21 (m, 4H, CH2), 1.88ꢀ1.91 (m, 6H, CH2), 3.14 (br s, 4H, CH2), 5.07 (br s,
1H, CH), 7.61 (t, 2H, Ar), 7.75 (t, 1H, Ar), 8.08 (t, 2H, Ar); Anal. Calcd for
(C16H23NO—C2H2O4) C, 64.46; H, 7.51; N, 4.18. Found: C, 64.29; H, 7.28; N, 4.33.
2-Cyclopentyl-1-phenyl-2-(pyrrolidin-1-yl)ethanone Hydrochloride (13). Pyrrolidine
(0.76 mL, 10.68 mmol) was added to a solution of 21 (0.95 g, 3.56 mmol) in a mixture of
anhydrous benzene (5 mL) and anhydrous Et2O (5 mL) at room temperature under an
N2 atmosphere. The reaction mixture was heated at 45 °C for 24 h, diluted with Et2O (15
mL), and washed with a saturated solution of NaHCO3 (2 × 10 mL). The organic portion
was extracted with HCl (1 N, 3 × 10 mL). The combined acidic portion was extracted
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with Et2O (10 mL), basified by addition of NaOH (5%, to pH 9–10) and reꢀextracted with
Et2O (3 × 15 mL). The combined organic portion was washed with brine (15 mL), dried
(Na2SO4), and solvent was removed under reduced pressure. The residual brown oil
was purified by flash chromatography (silica gel; hexanes:EtOAc; 95:5 to 75:25) to
afford the free base as a yellow oil. The free base was dissolved in a minimal amount of
anhydrous Et2O and converted to the hydrochloride salt by adding a saturated solution
of HCl gas in anhydrous Et2O (ca. 10 mL). The precipitate was recrystallized first from a
mixture of absolute EtOH/anhydrous Et2O and then the second time from a mixture of
acetone/absolute EtOH to afford 0.26 g (25%) of the product as lightꢀgrey crystals: mp
179–180 °C; 1H NMR (DMSOꢀd6) δ 1.05–1.24 (m, 2H, CH2), 1.40–1.51 (m, 4H, CH2),
1.55–1.67 (m, 1H, CH2), 1.82–2.06 (m, 5H, CH2), 2.41–2.50 (m, 1H, CH2), 3.04–3.16
(m, 1H, CH2), 3.22–3.32 (m, 1H, CH2), 3.39–3.49 (m, 1H, CH2), 3.64–3.75 (m, 1H, CH2),
5.59 (t, J = 7.1 Hz, 1H, CH), 7.64 (t, J = 7.7 Hz, 2H, ArH), 7.79 (t, J = 7.4 Hz, 1H, ArH),
8.13 (d, J = 7.7 Hz, 2H, ArH), 10.40 (br s, 1H, NH+ ex with D2O). Anal. Calcd for
(C17H23NO—HCl) C, 69.49; H, 8.23; N, 4.77. Found: C, 69.23; H, 8.06; N, 4.78.
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2-Cyclohexyl-1-phenyl-2-(pyrrolidin-1-yl)ethanone Hydrochloride (14). Pyrrolidine
(0.42 mL, 5.01 mmol) was added to a solution of 2ꢀbromoꢀ2ꢀcyclohexylꢀ1ꢀ
phenylethanone (22) (0.47 g, 1.67 mmol) in a mixture of anhydrous benzene (3 mL) and
anhydrous Et2O (3 mL) at room temperature under an N2 atmosphere. The reaction
mixture was allowed to stir at room temperature for 17 h, and then at reflux for 5 h.
Additional pyrrolidine (0.42 mL, 5.01 mmol) was added and the reaction mixture was
heated at 45 °C for 48 h. The reaction mixture was washed with a saturated solution of
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NaHCO3 (2 × 10 mL), H2O (10 mL). The organic portion was extracted with HCl (1 N, 3
× 5 mL). The combined acidic portion was basified with a solution of NaOH (5%, to pH
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10) and reꢀextracted with Et2O (3 × 10 mL). The combined organic portion was washed
with brine (10 mL), dried (Na2SO4) and solvent was removed under reduced pressure.
The obtained free base was converted to the hydrochloride salt and recrystallized twice
from a mixture of absolute EtOH/anhydrous Et2O to afford 0.19 g (37%) of the product
as beige crystals: mp 235–238 °C; 1H NMR (DMSOꢀd6) δ 0.58–0.58 (m, 1H, CH2),
0.74–0.92 (m, 2H, CH2), 1.19–1.22 (m, 2H, CH2), 1.52–1.73 (m, 4H, CH2), 1.92–2.10
(m, 6H, CH2), 3.05–3.66 (m, 4H, CH2), 5.56 (d, J = 5.9 Hz, 1H, CH), 7.63 (t, 2H, ArH),
7.79 (t, 1H, ArH), 8.11 (d, 2H, ArH), 10.30 (br s, 1H, NH+ ex with D2O). Anal. Calcd
(C18H25NO—HCl) C, 70.22; H, 8.51; N, 4.55. Found: C, 69.98; H, 8.33; N, 4.45.
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1-Phenyl-2-(piperidin-1-yl)pentan-1-one Hydrochloride (16). Piperidine (1.06 g,
12.45 mmol) was added to a stirred solution of 2ꢀbromoꢀ1ꢀphenylpentanꢀ1ꢀone (23)20
(1.00 g, 4.15 mmol) in a mixture of anhydrous benzene (5 mL) and anhydrous Et2O (5
mL), and the reaction mixture was heated at 45 °C for 20 h under an N2 atmosphere.
The reaction mixture was diluted with Et2O (10 mL) and washed with H2O (2 × 10 mL).
The organic portion was extracted with HCl (1 N, 3 × 10 mL). The combined acidic
portion was basified with NaOH (15%, to pH 9–10) and reꢀextracted with Et2O (3 × 15
mL). The combined organic portion was washed with brine (15 mL), dried (Na2SO4) and
solvent was removed under reduced pressure. The residue was purified by flash
chromatography (silica gel; hexane/EtOAc; 95:5) to afford a yellow oil. The oil was
converted to the hydrochloride salt by dissolving the free base in anhydrous Et2O and
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adding a saturated solution of gaseous HCl in Et2O (ca.10 mL). The salt was collected
by filtration and recrystallized from absolute EtOH to afford 0.65 g (56%) of the product
as white crystals: mp 191–193 °C (lit.27 mp 192 °C); 1H NMR (DMSOꢀd6) δ 0.80 (t, J =
7.2 Hz, 3H, CH3), 1.04–1.20 (m, 2H, CH2), 1.36–1.46 (m, 1H, CH2), 1.68–2.05 (m, 7H,
CH2), 2.99–3.15 (m, 2H, CH2), 3.24–3.36 (m, 1H, CH2), 3.61–3.64 (m, 1H, CH2), 5.36
(dd, J = 11.2, 7.4 Hz, 1H, CH), 7.63 (t, J = 7.6 Hz, 2H, ArH), 7.78 (t, J = 7.4 Hz, 1H,
ArH), 8.14 (d, J = 7.4 Hz, 2H, ArH), 10.18 (br s, 1H, NH+ ex with D2O).
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2-(Pyrrolidin-1-yl)-3,4-dihydronaphthalen-1(2H)-one Oxalate (17). A solution of 2ꢀ
Bromoꢀ3,4ꢀdihydronaphthalenꢀ1(2H)ꢀone28 (0.90 g, 4 mmol) in anhydrous benzene (3
mL) was added in a dropwise manner to a refluxing solution of pyrrolidine (0.85 g, 12
mmol) in anhydrous benzene (3 mL) under an N2 atmosphere. The reaction mixture was
heated at reflux for 15 min. After cooling to room temperature the reaction mixture was
diluted with Et2O (15 mL), washed with H2O (5 × 10 mL) and brine (10 mL). The organic
portion was extracted with HCl (1 N, 3 × 10 mL). The combined acidic portion was
washed with Et2O (15 mL), basified by addition of NaOH (15%, to pH ~ 10) and reꢀ
extracted with Et2O (3 × 15 mL). The combined organic portion was washed with H2O (2
× 15 mL), brine (15 mL), dried (MgSO4) and solvent was removed under reduced
pressure to afford a dark yellow oil (0.55 g). The oil was converted to its oxalate salt by
dissolving the free base in absolute EtOH and adding a solution of oxalic acid in Et2O.
The solution was stirred at room temperature for 2 h until the oxalate salt precipitated
and solidified. The grey solid was collected by filtration and recrystallized twice from
absolute EtOH to afford 0.14 g (11%) of the product as a grey powder: mp 139–143 °C;
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1H NMR (DMSOꢀd6) δ 1.93 (m, 4H, CH2), 2.24–2.34 (m, 1H, CH2), 2.47–2.50 (m, 1H,
CH2), 3.26–3.48 (m, 6H, CH2), 4.43–4.46 (m, 1H, CH), 7.40–7.44 (m, 2H, ArH), 7.64 (t,
1H, ArH), 7.92 (d, 1H, ArH). Anal. Calcd (C14H17NO—(COOH)2—0.25EtOH) C, 62.55; H,
6.52; N, 4.42. Found: C, 62.45; H, 6.33; N, 4.40.
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2-Bromo-2-cyclopentyl-1-phenylethanone (21). Bromine (0.04 mL, 0.79 mmol) was
added in one portion to a stirred solution of 2ꢀcyclopentylꢀ1ꢀphenylethanone (20)29 (0.70
g, 3.72 mmol) and AlCl3 (0.03 g, 0.20 mmol) in anhydrous Et2O (10 mL) at 0 °C (iceꢀ
bath) under an N2 atmosphere. The reaction mixture was allowed to warm to room
temperature and the remaining bromine (0.15 mL, 2.92 mmol) was added to the
reaction solution in a dropwise manner. The reaction mixture was neutralized with a
saturated solution of NaHCO3. The organic portion was separated, dried (Na2SO4), and
solvent was removed under reduced pressure to afford 0.97 g (98%) of the product as a
yellow oil. The compound was used without further characterization in the preparation of
compound 13.
2-Bromo-2-cyclohexyl-1-phenylethanone (22). This compound was synthesized
analogously to a published procedure30 except that aluminum chloride was used as
catalyst. The product was reported to be a paleꢀbrown oil.30
Bromine (0.02 mL, 0.4 mmol) was added in one portion to a stirred solution of 2ꢀ
cyclohexylꢀ1ꢀphenylethanone31 (0.405 g, 2.0 mmol) and AlCl3 (0.013 g, 0.1 mmol) in
anhydrous Et2O (5 mL) at 0 °C (iceꢀbath) under an N2 atmosphere. After 10 min the iceꢀ
bath was removed and the reaction mixture was allowed to warm to room temperature.
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The remaining bromine (0.08 mL, 1.6 mmol) was added to the reaction solution in a
dropwise manner over 5 min, and then the solution was neutralized with a saturated
solution of sodium NaHCO3. The organic layer was separated and the aqueous layer
was extracted with Et2O (3 × 10 mL). The combined organic portion was dried (Na2SO4)
and solvent was removed under reduced pressure to afford 0.470 g (83%) of the
product as a yellow solid: mp 49–52 °C. Compound 22 was used without further
purification in the preparation of 14.
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Correlational studies
Quantitative structureꢀactivity relationship studies were performed using the αꢀ
substituent volume and lipophilicity; volume (Vol) was calculated using SYBYLꢀX 2.1
(Tripos Inc., St. Louis, MO). Lipophilicity (π) values were obtained from the primary
literature.32 Linear regressions and statistical analyses were performed between both
these parameters and in vitro reuptake inhibition potency at DAT (pIC50 values) using
the software Prism 5.04 (GraphPad, San Diego, CA, USA), and correlations with a p <
0.05 were considered statistically significant. (pIC50 values, volume, and π values used
in this investigation are shown in Table S1.)
In Vitro Reuptake Assays
Subjects. Male SpragueꢀDawley rats (Charles River, Wilmington, MA, USA) weighing
250ꢀ350 g were housed three per cage with free access to food and water and
maintained on a 12 h light/dark cycle with lights on from 7:00 a.m. to 7:00 p.m. Animal
facilities were accredited by the Association for the Assessment and Accreditation of
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Laboratory Animal Care, and procedures were carried out in accordance with the
Institutional Animal Care and Use Committee and the National Institutes of Health
guidelines on care and use of animal subjects in research (National Research Council,
2011).
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Procedure. [3H]Transmitters (specific activity ranging from 30ꢀ50 Ci/mmol) were
purchased from Perkin Elmer (Shelton, CT, USA). All other chemicals and reagents
were acquired from SigmaꢀAldrich (St. Louis, MO, USA). Rats were euthanized by CO2
narcosis, and brains were processed to yield synaptosomes as previously described.33
Rat caudate tissue was used for DAT assays, whereas rat whole brain minus caudate
and cerebellum was used for SERT assays. In uptake inhibition assays, 5 nM
[3H]dopamine and 5 nM [3H]serotonin were used to assess transport activity at DAT and
SERT, respectively. The selectivity of uptake assays was optimized for a single
transporter by including unlabeled blockers to prevent uptake of [3H]transmitter by
competing transporters. Uptake inhibition assays were initiated by adding 100 ꢁL of
tissue suspension to 900 ꢁL Krebsꢀphosphate buffer (126 mM NaCl, 2.4 mM KCl, 0.83
mM CaCl2, 0.8 mM MgCl2, 0.5 mM KH2PO4, 0.5 mM Na2SO4, 11.1 mM glucose, 0.05
mM pargyline, 1mg/mL bovine serum albumin, and 1 mg/mL ascorbic acid, pH 7.4)
containing test drug and [3H]transmitter. Uptake inhibition assays were terminated by
rapid vacuum filtration through Whatman GF/B filters, and retained radioactivity was
quantified by liquid scintillation counting. Statistical analyses were carried out using
GraphPad Prism (v. 6.0; GraphPad Scientific, San Diego, CA, USA). IC50 values for
inhibition of reuptake were calculated based on nonꢀlinear regression analysis.
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Acknowledgments: This work was supported in part by PHS grant DA033930 and by
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the Intramural Program of the National Institute on Drug Abuse.
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Supporting Information Available: The supporting information includes pIC50 values,
volume, and π values used in the QSAR investigation. This information is available free
of charge via the Internet at http://pubs.acs.org/.
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TOC Graphic
Potency as DAT inhibitors:
Pyrrolidine > Piperidine
Improves with increasing
bulk/lipophilicity
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