Current Topics in Medicinal Chemistry - Volume 2, Issue 6, 2002

5-hydroxytryptamine (5-HT serotonin) is a neurotransmitter essential for a large number of physiological processes including the regulation of vascular and non-vascular smooth muscle contraction, modulation of platelet aggregation, and the regulation of appetite, mood, anxiety, wakefulness and perception. To mediate this astonishing array of functions, no fewer than 15 separate receptors have evolved, of which Read More

Several lines of evidence indicate that G-protein coupled receptors (GPCR) may exist in a state that allows a tonic level of stimulation in vivo (constitutive activity). Several native forms of GPCR, when expressed in recombinant cell lines, display significant signal transduction stimulation in the absence of activating ligand. Many GPCR, including three serotonin receptors, display robust constitutive activation upon the mutatio Read More

The structures of ketanserin (1) and spiperone (2) were examined in detail to determine the role of various substituent groups on 5-HT2A receptor affinity and selectivity. It was found that the presence of the quinazoline ring of ketanserin detracts from selectivity and that various ring-opened analogs displayed ketanserin-like affinity and up to 30-fold enhanced selectivity. The triazaspirodecanone portion of spiperone is a major Read More

The human 5-HT1B and 5-HT1D receptors are especially similar in sequence despite being encoded by two distinct genes. Although, human 5-HT1B and 5-HT1D receptors have been pharmacologically differentiated using nonselective 5-HT1B / D receptor antagonists such as ketanserin (1), ritanserin (2) and methiothepin (3), the precise function of these receptors remains undefined, and progress toward this has been hamp Read More

The present review describes our approach to the development of a structurally unique class of 5- HT2A ligands. On the basis of an abbreviated graphics model of a 5-HT2A serotonin receptor, it was hypothesized that introduction of an additional aromatic ring might enhance the affinity of phenylethylamine (an agent that lacks significant affinity for the 5-HT2A receptors). Continued work with such structures, and the contin Read More

The serotonin 5-HT3 receptor subtype is unique among the receptors for this neurotransmitter because it has been demonstrated to be a ligand-gated ion channel capable of mediating rapid intercellular communication. This review covers the authors'work performed during more than a decade in the development of 5-HT3 receptor ligands belonging to the classes of arylpiperazines, tropanes, and quinuclidine derivatives. Read More

Among serotonin receptors (5-HTRs), the 5-HT4 subtype is of considerable interest because it is involved in (patho)physiological processes both in peripheral and central nervous systems. In addition to the clinical use of 5-HT4R agonists in the treatment of gastrointestinal motility disorders, the potential use of antagonists in the treatment of irritable bowel syndrome, arrhythmias and micturition disturbances are currently under i Read More

The possible role of 5-HT6 receptor antagonists in the treatment of learning and memory disorders has stimulated significant recent work in this area. The first selective antagonists of this receptor were identified by Roche (Ro 04-6790 and Ro 63-0563) and SmithKline Beecham (SB-271046), although they only had poor to modest brain penetration, respectively. Recently, several structurally different series of selective antagon Read More