title: Benzylimidazolines as h5-HT1B/1D serotonin receptor ligands: a structure-affinity investigation.
abstract: Benzylimidazolines may represent a class of 5-HT1D ligands that has yet to be exploited. On the basis of a previous report that the 2-(substituted-benzyl)imidazoline alpha-adrenergic agonist oxymetazoline (8) binds with high affinity at calf brain 5-HT1D receptors, we explored the structure-affinity relationships of a series of related derivatives. Each of the aromatic substituents was removed and then reinstated in a systematic manner to determine the influence of the individual substituents on binding. It was found that all of the aromatic substituents of 8 act in concert to impart high affinity. However, although the 3-hydroxy group could be removed without significantly reducing affinity for h5-HT1D (i.e., human 5-HT1Dalpha) receptors, this modification reduced h5-HT1B (i.e., human 5-HT1Dbeta) receptor affinity by nearly 50-fold. The 2, 6-dimethyl groups also contribute to binding but seem to play a greater role for h5-HT1B binding than h5-HT1D binding. With the appropriate structural modifications, several compounds were identified that display 20- to >100-fold selectivity for h5-HT1D versus h5-HT1B receptors. Preliminary functional data suggest that these compounds behave as agonists. Given that 5-HT1D agonists are currently being explored for their antimigraine action and that activation of h5-HT1B receptors might be associated with cardiovascular side effects, h5-HT1D-selective agents may offer a new lead for the development of therapeutically efficacious agents.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298-0540, USA.
authors.forename: H
authors.initials: H
authors.lastname: Law
authors.forename: M
authors.initials: M
authors.lastname: Dukat
authors.forename: M
authors.initials: M
authors.lastname: Teitler
authors.forename: D K
authors.initials: DK
authors.lastname: Lee
authors.forename: L
authors.initials: L
authors.lastname: Mazzocco
authors.forename: R
authors.initials: R
authors.lastname: Kamboj
authors.forename: V
authors.initials: V
authors.lastname: Rampersad
authors.forename: T
authors.initials: T
authors.lastname: Prisinzano
authors.forename: R A
authors.initials: RA
authors.lastname: Glennon
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008024:Ligands; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010109:Oxymetazoline / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012501:Saphenous Vein / Q000187:drug effects / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000316:Adrenergic alpha-Agonists; C470302:HTR1B protein, human; D008024:Ligands; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011942:Receptors, Adrenergic, alpha; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D010109:Oxymetazoline; D000242:Cyclic AMP