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q PHILIP MORRIS U. S. A. INTER-OFF'IC'E CORR'ESP'ONDEN'CE Richmond, Virginia To: R. Carchman Date: October 3, 1991 From: R. Southwick Subject: CandidateSt'imuIantsf'orTrigeminalScreening In 11989, an examination of a variety of stimulants was carried out to ascertain whether subjective testing of trigeminal stimulants was feasible. A panel was established to operate using the same prot'oco1as the Odor Profile panel. A list of 17 descriptors was created~ which encompassed all known aspects of trigeminal response. Using a 5-point scale, stimuli which:received a high score for one or more descriptors would'e then be considered' "trigeminal" whereas low scores on all descriptorswould result in classifying the compound as "non-trigeminall" The stimuli were selected from the odor database by searching for compounds with high scores for cooling, pungent, ammonia, or spicy. This list was augmented! with compounds described by Leffingwell' as being harsh or having body and compounds in Arctander havin~ odor or flavor descriptions suggestive of trigeminal effects. A final pool of more than 150 stimuli was assembled from which 30 were selected for screening. Representative compounds such as a tertiary amine, carboxylic acid, amide etc. were included as well as 5 stimuli which probably were "non-trigeminal" (olfactory)'. Evaluation of the panel data for these 30 representative stimulant~sled to the following conclusions: 1. Trigeminal and olfactory stimulants could be differentiatedi Vanillhn (olfactory) mapped along the vector "dulls"whereas acetic acid! ('trigeminal)appeared as pungent. 2. The odor profiling database can be used to select candidat'es: Descriptors which were found to reflect trigeminal response include "cooling," "like ammonia,"' "sour acid," "sharp; pungent" and "black pepper-like." 3. Different classes of trigeminal stimuli~were separated': Acetic acid (pungent), menthol (cool) and nicotine (prickly) mapped into different quadrants. Based oni these conclusions, initial trigerninal screening,could include someof t!hee stimuli described in this study. In particular, vanillin (non-trigeminal)s rnenthol'. (trigeminal, cooling), acetic acid'i ('trigeminal, pungent) and nicotine (t~rigen3inal, prickly)

%h% exhibit a broad range of response. This would establish that the screening assays give the same or better degree of discrimination as does a human~panel. Of nearly 30 compounds tested, only four mapped near nicotine in the trigeminEil multi-dimensional space. This reflects the skill involved! in the selection of candidate stimuli. Interestingly, none of the 4 compounds (n-butylidenephthalide, pyridine phenylacetic acid', and 1-(3-rnethylbutyryl) pyrrolidine have the same functional group and, with the exception of pyridine, all differ frominicotine as well. They were perceived to be as "prickly" as nicotine but none of these exhibitedl the full sensory properties of nicotine in subjective testing in cigarettes. /ds 4~S~ cc: H. Grubbs Y. Houminer J. Seeman