794
U. Laban et al. / Bioorg. Med. Chem. Lett. 11 (2001) 793–795
receptor subtypes. Substitution of the dimethyl func-
tionality in 1 with a pyrrolidyl (2) results in a doubling
of 5-HT1A affinity, as well as an increased selectivity for
5-HT1A/5-HT2 binding. Compound 2 is more potent
than the standard 5-HT1A agonist 8-hydroxy-2-(N,N-
dipropylamino)tetralin (8-OH-DPAT) at this site and
has potency nearly comparable to the partial ergoline
LY293284.9 An agonist effect at serotonin 5-HT2A sites
is believed responsible for the hallucinogenic proper-
ties10 of various drugs, while stimulation of 5-HT1A sites
results in anxiolytic effects.2
The behavioral effects of drugs acting at 5-HT1A/2A
receptors may be quantified using the two lever drug
discrimination procedure (DD).11 In these experiments
we employed two hallucinogenic training drugs, LSD
and DOI (2,5-dimethoxy-4-iodoamphetamine),1 and the
5-HT1A agonist LY293284.1 Animals were trained on a
food-reinforced FR50 schedule. Drug discrimination
data for hallucinogen-like activity are shown in Tables 2
and 3. The fluorotryptamine 2 fails to substitute in
either LSD- or DOI-trained rats, consistent with its low
affinity for 5-HT2A receptors, whereas in LY293284-
trained rats (Table 4) full substitution occurs at doses of
1 mmol/kg. This latter result is indicative of in vivo full
agonism of compound 2 at the serotonin 5-HT1A
receptor subtype, an observation we have previously
made for compound 1.1
Compound 2 (at 0.046 mg/kg and higher) induced a
pronounced serotonin syndrome (i.e., flat body posture
and forepaw treading) that affected response rates,
causing behavioral disruption. These effects are char-
acteristic of agonist stimulation of the 5-HT1A receptor
in rats.
In conclusion, we have shown that 4-fluoro-5-methoxy-
tryptamines possess potent 5-HT1A activity. Although
compound 2 represents a further potency enhancement
over the N,N-dimethyl analogue 1, more potent con-
geners may exist. More importantly, general pharmaco-
logical studies of agonist effects at the 5-HT1A receptor
are almost exclusively carried out with the single agent
8-OH-DPAT. The new molecules reported herein offer
pharmacologists the opportunity to employ an agonist
from a different chemical class that possesses enhanced
potency and potentially enhanced selectivity. Further
characterization of compound 2, particularly for affinity
at other receptor types, is currently underway.
Scheme 1. (a) (CH3)2NCH(OCH3)2, pyrrolidine, DMF, reflux 3 h,
77%; (b) H2, Pd/C, 84%; (c) (i) NaHSO3, rt, 24 h; (ii) Ac2O, 3 h, reflux
50%; (d) (i) Br2, H2O, 0 ꢀC; (ii) 5 N aq NaOH, 75%; (e) NaOMe, CuI,
CH3CO2Et, 5 h, sealed tube, 140 ꢀC, 70%; (f) (i) (CO)2Cl2, Et2O, 0.5 h,
0 ꢀC; (ii) pyrrolidine, 24 h, rt, 72%. (g) LAH, dioxane, 24 h, 90 ꢀC,
69%.
Table 1. Results of radioligand competition studies at [125I] DOI-
labeled cloned rat 5-HT2A, rat 5-HT2C, and [3H]8-OH-DPAT-labeled
human 5-HT1A receptors (Ki valuesÆSEM in nanomolar)
Table 3. Data from substitution tests in DOI-trained rats
a
Compd
5-HT2A
5-HT2C
5-HT1A
Drug
Dose
mmol/kg
N
% D
% SDL
ED50 (95% C.I.)
mmol/kg
1
2
122Æ14.2
130Æ3.2
55Æ9.4
0.23Æ0.03
0.12Æ0.012
0.83Æ0.093b
0.053Æ0.012
140Æ8.4
DOI
10
0.29
(0.19–0.43)
8-OH DPAT
LY293284
2
0.125
0.25
0.50
9
10
9
22
30
50
0
29
50
aValues are means of three experiments, standard deviation is given in
parentheses.
bKD value.
N.S.
Table 4. Data from substitution tests in LY293284-trained rats
Table 2. Data from substitution tests in LSD-trained rats
Drug
Dose
mmol/kg
N
% D % SDL ED50 (95% C.I.)
mmol/kg
Drug
Dose
mmol/kg
Na
% Db
% SDLc
ED50 (95% C.I.)
mmol/kg
LY293284
8-OH-DPAT
2
10
10
0.031
(0.02–0.05)
0.099
LSD
2
15
10
15
10
9
0.026 (0.014–0.045)
N.S.d
0.125
0.25
0.5
10
53
60
78
11
57
75
67
(0.06–0.20)
0.063
0.125
0.250
0.50
8
10
8
9
10
0
10
12.5
66.6
90
25
0.091a
(0.064–0.12)
1.0
66.6
100
100
100
aNumber of animals tested at each dose.
bPercentage of animals that failed to emit 50 responses within 5 min.
cPercentage of animals tested that selected the training drug appro-
priate lever.
1.0
aOnly the three lower doses were used to calculate the ED50 because
the higher doses produced greater than 50% disruption of responding.
dNo substitution occurred.