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DEPARTMENT.OFPHARMACOLOGY. RICHMOND.. VIRGINIA.23219 ..July 12, 1967 Dr. Robert C. Hockett Associate Scientific Director The Council for Tobacco Research - U.S.A. 633 Third Avenue New York, N. Y. 10017 Dear Bob: I am enclosing an application that describes in a brief way research thoughts in~the general area of nicotine metabolism. We are very tardy in submitting this application. The reason, in part, has been our desire to run through some preliminary or range-finding experiments and to establish a feeling that we are on the right course and had developed sufficiently workable techniques so that contemplated work could proceed without delay. We now feel that this is the case and hope that the Council will see fit to consider our application, which in many ways is a continuation, with more of an emphasis on biological and enzymatic studies -- in contrast to much of the earlier work in which we concentrated on the problems of structure and syntheses of many of the nicotine metabolites. To bring you up-to-date in an informal way on some of the more recent happenings that have not yet been reduced to manuscript or report form a few comments will be made. ~ Preliminary experiments were conducted on the effect of age on the ~ ability of rat-microsomal preparations to metabolize nicotine. Using our Q younger rats (150-200g) as a standard it appeared quite consistently that Cj equivalent weights of the liver fractions from the older animals (400-500g) CA showed a lesser ability to metabolize nicotine. Studies to relate this ~ apparent deficit to the composition of the liver fraction and comparative ~ studies on the ability of animals of varying ages to metabolize labelled ~ nicotine are contemplated. Isotopic material is already on~hand for these ~ studies. At earlier dates we talked about the progress made on the electron-capture studics with pentafluropropionylmetanicotine that had been derived from nicotine and pentafluropropionic acid anhydri~de as a basis for the quantitative determination of nicotine (with support from the kMA Education and Research Foundation). The major drawbacks to the analytical method, in our goal to reach 1 x 10-12 grams included a broad peak which could not be sharpened by .. . . . . . - . _. . -._. .. . -._. .. .J:..r._._. . _ «~-....a......... .. ._.«~......-.r...

Dr. Hockett Page Two • July 12, 1967 increasing column temperature because of the backgroundor trash that appeared in biological material. This problem seems to have been overcome in part by modification of the injection part of the apparatus (a standard procedure). Additionally, the basic chemistry of the reaction has been extended to nornicotine. The analytical sample of pentafluropropionylmetanicotine (by analysis) shows a retention time different from that of the corresponding nicotine derivative. In consequence we feel more and more secure about the method. In the midst of other things we are setting up to run kinetic studies on the conversion of y-3-pyridyl-y-methylaminobutyric acidito cotinine. At least at physiological pH ranges this should be relatively simple to accomplish polarimetrically in view of the marked differences in the specific rotations of the two compounds. The data should help persuade people of the care needed in isolating cotinine. We shall be grateful as always for any considerationigiven to our application. A copy with the signature of the college business officer will follow. Please do not hesitate to write or phone in the event of any questions. We are grateful for the generous and helpful support of the past and' close with our best personal wishes. Sincerely, Herbert McKennis, Jr. HMcK/bb