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Many central nervous system (CNS) diseases and disorders remain very difficult to treat because of the limiting effect of blood-brain barrier (BBB) on delivery of drugs into the CNS. A limited brain-uptake prevents numerous, otherwise promising agents to become pharmaceutically useful entities. Neuropeptides, their analogues and peptidomimetics are typical of these agents. Besides their poor BBB penetration, size, innate water-solubility and absence of specific transport systems to ferry them into the brain parenchyma, most peptides also have short biological half-lives because of rapid metabolism and clearance from the body [1].

Fleur L. Strand: Neuropeptides: general characteristics and neuropharmaceutical potential in treating CNS disorders.- David J. Begley and Milton W. Brightman: Structural and functional aspects of the blood-brain barrier.- Abba J. Kastin and Weihong Pan: Peptide transport across the blood-brain barrier.- Intracranial delivery of proteins and peptides as a therapy for neurodegenerative diseases.- David Fortin: Altering the properties of the blood-brain barrier: disruption and permeabilization.- Katalin Prokai-Tatrai and Laszlo Prokai: Modifying peptide properties by prodrug design for enhanced transport into the CNS.- Suresh P. Vyas: CNS-delivery via conjugation to biological carriers: physiological-based approaches.- Jamal Temsamani and Jean-Michel Scherrmann: Peptide vectors as drug carriers. Index Vol. 61.

Few agents (agonists) bind at [3H]nicotine-labeled nicotine receptors with an affinity comparable to that of nicotine. We initially approached this problem by undertaking a systematic structure-affinity study to determine the contribution to binding of various aspects of the nicotine molecule and of nicotine-related derivatives. For example a series of aryl-substituted and unsubstituted, primary, secondary, and tertiary amine derivatives of 3-(aminomethyl)pyridine (1) were prepared and examined. The finding that 1 (R = Me, R’ = Et, X = H) binds with good affinity (Ki = 28 nM) led to the synthesis of several conformationally-restricted analogs, such as 2 and 3 (Ki = 85 and 12 nM, respectively). With the availability of such structure-affinity and conformational data, it should now be possible to optimize affintiy by design and synthesis of new compounds. (Supported in part by funding from TDC/CIT.)