Product Design
Nicotine Pharmacology As Influenced by Structural Modification: Biological Effects Elucidated by Chemical Reaction Modeling
Abstract
States that the biological activity and pharmacology of nicotine can be altered with small changes in it's molecular structure. Indicates these changes are little understood and says the use of chemical reaction models would be beneficial in elucidating this phenomena.
Fields
- Notes
Draft material.
- Author
- Dwyer, R. William (Associate Prinicipal Scientist, PM, c. Fe.b '97)Reported to Robert A Fenner, Dir. of Product Research, Richmond VA
- Osdene, Thomas Stefan, Ph.D. (Director of Science and Technology, Philip Morris [1986])
Ph.D. in Organic Chemistry. Ten years of research when he started with PM in 1965. Worked in Chemical Research Division of PM 1965-66; Chemical and Biological Research Division 1966-69; Director of Research 1969-1984, also assumed independent position as Director of Research and Extramural Studies during these years; became Director of Science and Technology in 1984, reporting directly to Philip Morris USA Executive VP Mark Serrano. Involved with Center for Indoor Air Research (CIAR) 1988. Attended PM's Operation Downunder Conference in June, 1987. Retired 1993.- Sanders, Edward B. (Ted), Ph.D. (PM Dir. of Chemical Research)
Neuchatel, '99- Secor, Henry V. (PM Researcher, 1980s)
Dr. Secor was a Researcher for Philip Morris. In the early to mid 1980's Dr. Secor made the nicotine analogs used in Victor DeNoble's studies. (V. DeNoble 5-26-94)- Seeman, Jeffrey I., Ph.D. (PM scientist -- nicotine analogs)
Defense - Osdene, Thomas Stefan, Ph.D. (Director of Science and Technology, Philip Morris [1986])
- Hypothesis
- Nicotine transport, transfer, and uptakeDesign changes which alter nicotine delivery or effect how the product causes and maintains dependence, including transfer of nicotine from tobacco to smoke, and uptake into the body.
- Smoke constituent testing
Development of methods for measurement of gas and particulate yields in mainstream and sidestream smoke.- Smoking psychology and behavior
- Smoke constituent testing
- Keyword
- Animal testing
- Brain activity
- Central nervous system (CNS)
- Electrophysiological
- Neuropharmacology (Electrophysiology)
Receptor, brain, and CNS effects (EEG, trigeminal response, etc.)- Nicotine delivery (Smoke nicotine or nicotine yield)
- Physiological effects
- Sensory response
- Brain activity
- Additive
- 2-methylnicotine
- 4-methylnicotine
- Smoke Constituent
- 2-methylnicotine
- 4-methylnicotine
- Nicotine
- Nicotinoids
- 4-methylnicotine
- Design Component
- Nicotine content (Tobacco nicotine content)Total nicotine in the unburnt tobacco rod
- Named Organization
- Philip Morris Research Center (Did 1983 study which concluded that nicotine is addictive)Philip Morris Research Center did a 1983 study which concluded that nicotine is addictive, per New York Times (Reuters 4/5/94).
- Subject
- CNS/Brain (Effects)
- nicotine technology
- nicotine analogues (Technology)
- Pharmacology (Effects)
- Test/Animal Subject (Testing)
- nicotine technology
Document Images
13
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.Activities of Nicotine Analogues8
GUINEA_PIG ILEUM
Compound
LDso b
(mg/kg)[n]c Relative Activity
WithoHt
Antagonist [n]e
(S)-Nicotinei 0.42±0.04[58]c 1.3±0.3[4)
(R,S)-Nicotine (1) 0.90±0.09[60] < 0.54#.18[4]
(R,S)-2-Methylnicotine (2) 91t5[40] 7.0±3.0x10-4[3]
(R,S)-cis-3'-Methylnicotine (3'c) 23.7±1.4[50) 1.5±0.6x10-2[3]
(R,S)-trans-.3'-.Methynicotine(3't) 16.2±0.7[60] 1.7t0.7x10-2[3)
(R,S)-4-Methylnicotine (4) 32t3[40] 10#2x10-3[2] '
(R,S)-5-Methylnicotine (5) 3.5t0.7[70] 0.6#0.4[3]
(R,S)-6-Methylnicotine (6) 0.13±0.02[40] 1.7+.25[3)
(S)-cis-5'-Methylnicotine (5~'c,) 61.9±3.6[50] 2..1x10-3[2]k
% Reduction of Contraction
Pretreatmente ~tith Pretreatment With Rat Blood h
Atrop_ine ' Hexamethonium Pressure (mg/kg) [n]
29[3]e 82[6]e
55[4] 58[6]
45[4] 37[8]
52[3] 73[61
65[3] 74[61
81[3] .5[4]
46[3] 73[4]
50[3] 84[6)
30(4] 8[6]
.041±.010[101
.058±.012[141
j
6.3±3.1[11]
2.81±.06[8]
310t260[13]
0.27+.12[151
0..0449±.0016[51
1
51#46[9]
(a) See footnote 4. (b) Route of administration was i.v. (free base) in male albino mice (SPF).
Values
calculated using the method of D. J. Finney, "Probit Analysis," Cambridge, 1952. (c) [n] refers to
number of
animals. (d) Molar ratio of standard (1-nicotine dihydrogen tartrate) to test compound which causes
an
: equivalent response. Each experiment used a freshly prepared ileum strip. The mean (±standard
deviation) dose
of the standard which caused an 8 mm contraction involved a 50 mL solution of 1.00±0.33 g/mL
1-nicotine
dihydrogen tartrate. The procedure used is based on R. Magnus, Pfluegers Archiv., 102, 123 (1904).
(e) [n]
refers to the number of replicates. (f) Atropine sulfate, 2.15 x 10 8 g/ml. (g) Hexamethonium
iodide, 2.15 x
10 5 g/ml. (h) Dose necessary to cause a 25% increase in blood pressure by infusion into the
cannulated
jugular vein. (i) For some recent results on the pharmacology of (S)-nicotine, see M. D. Aceto, et.
al.,
J. Med. Chem., 22, 174 (1979). (j) No blood pressure increase up to 31 mg/kg for 2. (k) A bery large
error
associated with this value, two determinations made. (1) Data obtained on (S)-6-methylnicotine.
ejsszioOo4
Table
Compound
Nicotine
2-Methylnicotine
4-Methylnicotine
5-Methylnicotine
6-Methylnicotine
cis-3'-Methylnicotine
trans-3'--rlethylnicotine
12
INDO Calculated Parameters and Relative Aklylation
Rates of Nicotine and Nicotine Analogues.
Calculated Conformational
Parameters
~
t Degreesa'b ,o+atiuna~
Minima Maxima Barriers
(1) 280/100 340/160'' 1.0/1.0
(2) 100/240 360/160 2.5/1.7
(4) 280/100 180/340 2,9/1..9 .
(5) 280/100 160/340 1.0/1.0
(6) 280/100 340/160 1.0/1.0
(3,~yc) 100/280 180/360 4.5/4.4
(3,M't) 280/100 340/160 1.0/1.0
i
Pyridine (N) and Pyrrolidine (N') Alkylations
2.7±.36
2.3#.12
0.33+.03
2.5±.24
10.±.30 .'
Relative Partial Rate FactorfI
fN fN'
0.37 1-
0. 108 'i 0.23f
0.768 0.25f
0.64g 1.6f
0.16f 1.6h
(a) t=(C4-C3-C2,-C3,) dihedral angle. Clo9kwise rotation of the pyrrolidine ring relative to the
pyridine ring is in the "positive" sense. (b) For each pair, the lower energy conformation is listed
first. (c) The order corresponds t low r ene gy minimum to lower energy maximum, followed by higher
a~ t`n c ~i
minirzum to higher maximum. See text, for a discussion. (d) kN, is the Wins tein-Holnes s rate
constant
and reflects the total rate of pyrrolidine alkylation [c.f. J. I. Seeman and W. A. Farone, J. Org.
Chem.,
43, 1954 (1978); J. I. Seeman, E. B. Sanders, and W. A. Farone, Tetrahedron, 36, 1173.(1980)]. (e)
Determined by nmr analysis of the total reaction product of the alkaloid and iodomethane in
acetonitrile at 25°. (f) Calculated from kN,/kN = fN,/fN for each analogue, where f refers to
partial
rate factor. (g) Derived from the relative rates of pyridine and substituted pyridine iodomethyla-
tions in acetonitrile at 25°; pyridine:2-methylpyridinel,.-)
-methylpyridine:4-methylpyridine.-'1,3-
dimethylpyridine = 1:0.43:1.7:2.1:0.43. (h) Assumed that fN,(6) = fN,(5). (i) Buttressing effects
taken into consideration.
1
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