DOPAMINE receptors belong to the family of G protein-coupled receptors. On the basis of the homology between these receptors, three different dopamine receptors (D1,D2,D3) have been cloned1–7. Dopamine receptors are primary targets for drugs used in the treatment of psychomotor disorders such as Parkinson's disease and schizophrenia8,9. In the management of socially withdrawn and treatment-resistant schizophrenics, clozapine10 is one of the most favoured antipsychotics because it does not cause tardive dyskinesia11. Clozapine, however, has dissociation constants for binding to D2 and D3 that are 4 to 30 times the therapeutic free concentration of clozapine in plasma water12,13. This observation suggests the existence of other types of dopamine receptors which are more sensitive to clozapine. Here we report the cloning of a gene that encodes such a receptor (D4). The D4 receptor gene has high homology to the human dopamine D2 and D3 receptor genes. The pharmacological characteristics of this receptor resembles that of the D2 and D3 receptors, but its affinity for clozapine is one order of magnitude higher. Recognition and characterization of this clozapine neuroleptic site may prove useful in the design of new types of drugs.

Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine.

The Henry reaction: recent examples

Heteroatoms as well as heterocyclic scaffolds are frequently present as the common cores in a plethora of active pharmaceuticals natural products. Statistically, more than 85% of all biologically active compounds are heterocycles or comprise a heterocycle and most frequently, nitrogen heterocycles as a backbone in their complex structures. These facts disclose and emphasize the vital role of heterocycles in modern drug design and drug discovery. In this review, we try to present a comprehensive overview of top prescribed drugs containing nitrogen heterocycles, describing their pharmacological properties, medical applications and their selected synthetic pathways. It is worth mentioning that the reported examples are actually limited to current top selling drugs, being or containing N-heterocycles and their synthetic information has been extracted from both scientific journals and the wider patent literature.

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Prescribed drugs containing nitrogen heterocycles: an overview

1. Introdution A 2. Early Developments B 2.1. First Reports B 2.2. Heterocycle Synthesis E 2.3. Nitroalkene Synthesis G 2.4. Synthesis of Dinitroamines G 2.5. Reactions with Preformed Imines H 2.6. Conjugate Addition Nitro-Mannich Reactions H 2.7. Reactions of Nitroesters I 3. Noncatayltic Reactions J 3.1. Base-Mediated Reactions J 3.2. Reactions of α-Amido Sulfones K 3.3. Auxiliary Controlled Stereoselective Reactions L 3.4. Reformatsky-Type Reactions M 3.5. Electrochemically Induced Nitro-Mannich Reactions N 4. Indirect Metal-Catalyzed Reactions N 4.1. Racemic Reactions N 4.2. Asymmetric Reactions N 5. Direct Metal-Catalyzed Reactions O 5.1. Racemic Reactions O 5.2. Asymmetric Reactions P 6. Organocatalytic Reactions T 6.1. Racemic Reactions T 6.2. Asymmetric Reactions U 6.2.1. Urea/Thiourea Catalysts U 6.2.2. Brønsted Acid Catalysts X 6.2.3. Phase-Transfer Catalysts Y 6.2.4. Brønsted-Base Catalysts Z 7. Reactions of Ketimines AA 7.1. Racemic Reactions AA 7.2. Auxiliary Controlled Reactions AB 7.3. Catalytic Enantioselective Reactions AB 8. Reactions of α-Nitroesters AC 9. Reactions of α-Nitrophosphonates AE 10. Conjugate Addition Nitro-Mannich Reactions AF 10.1. Organocatalytic Reactions of Carbon Nucleophiles AF 10.2. Reactions with Organometallic Nucleophiles AG 10.3. Aza-Morita−Baylis−Hillman Reactions AI 10.4. Synthesis of 3-Nitrochromene Derivatives AI 10.5. [3 + 2] Cycloadditions AJ 10.6. [2 + 2] Cycloadditions AL 11. Cascade Reactions AL 11.1. Nitro-Mannich/Lactamization Cascades AL 11.2. Other Cascade Reactions AO 12. Cross-Dehydrogenative Coupling Reactions AP 13. Miscellaneous Reactions AQ 13.1. Reactions of Isoquinolines AQ 13.2. Reactions of Trinitromethane AR 14. Applications to Synthesis AR 14.1. Peptide Synthesis AU 15. Summary AU Author Information AW Corresponding Author AW Notes AW Biographies AW Acknowledgments AX References AX

Nitro-Mannich reaction.

Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain sulfonamide or sulfonamide functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.

Sulfonamide and sulfamide substituted imidazoquinolines

Chemical and pharmacological investigations of some .omega.-substituted alkylamino-3-aminopyridines

Agents acting on the central nervous system. 15. 2-Substituted 1,2,3,4,6,7,12,12a-octahydropyrazino(2',1':6,1)pyrido(3,4-b)indoles. A new class of central nervous system depressants.

Neuroleptic receptors: stereoselectivity for neuroleptic enantiomers.

A Novel Synthesis of Substituted 2-Oxopiperidines

The synthesis and pharmacological evaluation of	a number of 3-substituted 2,3,4,4a,5,6-hexahydro-1(H)-pyrazino are reported. Them compounds in general show hypotensive and adrenergic-receptor blocking activity. The hypotensive activity is particularly marked in 3-β-phenethy and 3-y-(p-fiuorobenxoy1)propy1-2,3,4,4a,5,6-hexahydrod-1(H)pyrazino[1,2-a]quinolines.

Padam C. Jain

Papers

Chemical and pharmacological investigations of some .omega.-substituted alkylamino-3-aminopyridines

Agents acting on the central nervous system. 15. 2-Substituted 1,2,3,4,6,7,12,12a-octahydropyrazino(2',1':6,1)pyrido(3,4-b)indoles. A new class of central nervous system depressants.

Neuroleptic receptors: stereoselectivity for neuroleptic enantiomers.

A Novel Synthesis of Substituted 2-Oxopiperidines

Agents acting on the central nervous system. XIII. 2,3,4,4a,5,6-Hexahydro-1(H)-pyrazino[1,2-a]quinolines. A new class of hypotensive agents