There are numerous medicinal chemistry reports in the literature describing the pharmacological properties of thousands of narcotics, stimulants, hallucinogens, sedative-hypnotic drugs, cannabinoids, and other psychoactive substances as well as synthetic methods for their preparations. This information, while essential for the advancement of science, has been used by clandestine chemists to manufacture and market an endless variety of analogs of so-called designer drugs. In this review, we describe how clandestine chemists used the principles of medicinal chemistry to design molecules, referred to as designer drugs, that elicit the effects of opioids, amphetamine and analogs, cannabinoids, and phencyclidine analogs while circumventing the law.

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The solid state structures of two synthetic opioid peptides have been determined by X-ray single crystal analysis. The first X-ray structure is that of N,N-diallyl-(O-t-butyl)-Tyr-Aib-Aib-Phe-Leu-OMe (RTI02), a protected derivative of the 5-receptor selective antagonist ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH. ICI 174,864 is one of a series of rationally designed Aib-substituted enkephalin analogs which have shown site-specific antagonist properties. The second compound, the tetrapeptide Tyr-Tic-Phe-Phe-OH (TIPP), is one of a family of linear peptides containing the conformationally restricted Tic residue (tetrahydroisoquinoline-3-carboxylic acid). TIPP exhibits high affinity, selectivity and antagonism for the 8-receptor, Crystals of both peptides were obtained by slow evaporation and found to be monoclinic in space group P2j. Unit cell dimensions for RTI02 were: a = 13.619(4)/~, b = 12.467(3)/~, c = 13.750(4)/~, [3 = 96.03(4) ° and V = 2322(1) A 3. The asymmetric unit contained one molecule of RTI02 and one molecule of methanol, giving a calculated density of 1.156 g cm -3. Unit cell dimensions for TIPP were: a = 8.879(5) ,~, b = 20.146(8) ,~, c = 12.710(6) ,~, [3 = 107.89(2) ° and V = 2164(2) ,~3 The asymmetric unit contained one molecule of TIPP and three molecules of acetic acid, giving a calculated density of 1.251 g cm -3. The RTI02 backbone has a double [3-bend, stabilized by two intramolecular hydrogen bonds. The TIPP backbone is also folded, but with only a single bend, stabilized by one intramolecular hydrogen bond and several hydrogen bonds to solvent molecules. Both compounds contain aromatic rings in close vicinity (4-6/~).

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The nociceptin/orphanin FQ opioid peptide (NOP) receptor is a widely expressed GPCR involved in the modulation of pain, anxiety, and motor behaviors. Dissecting the functional properties of this receptor is limited by the lack of systemically active ligands that are brain permeant. The small molecule NOP receptor-selective, full agonist 8-[(1S,3aS)-2,3,3a,4,5,6-hexahydro- 1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198) hydrochloride is an active, brain penetrant ligand, but its difficult and cost-prohibitive synthesis limits its widespread use and availability for animal studies. Here, we detail a more efficient and convenient method of synthesis, and use both in vitro and in vivo pharmacological assays to fully characterize this ligand. Specifically, we characterize the pharmacodynamics of Ro 64-6198 in cAMP and G-protein coupling in vitro and examine, for the first time, the effects of nociceptin/orphanin FQ and Ro 64-6198 in arrestin recruitment assays. Further, we examine the effects of Ro 64-6198 on analgesia, anxiety, and locomotor responses in vivo. This new synthesis and pharmacological characterization provide additional insights into the useful, systemically active, NOP receptor agonist Ro 64-6198.