The histamine H1-receptor antagonist binding site. Part I: Active conformation of cyproheptadine

Abstract

The active conformation of several histamine H1-antagonists is investigated. As a template molecule we used the antagonist cyproheptadine, which consists of a piperidylene ring connected to a tricyclic system. The piperidylene moiety is shown to be flexible. The global minimum is a chair conformation but, additionally, a second chair and various boat conformations have to be considered, as their energies are less than 5 kcal/mol above the energy of the global minimum. Two semi-rigid histamine H1-antagonists, phenindamine and triprolidine, were fitted onto the various conformations of cyproheptadine in order to derive the pharmacologically active conformation of cyproheptadine. At the same time, the active conformation of both phenindamine and triprolidine was derived. It is demonstrated that, within the receptor-bound conformation of cyproheptadine, the piperidylene ring most probably exists in a boat form.

The Histamine H1-Receptor Antagonist Binding Site. A Stereoselective Pharmacophoric Model Based upon (Semi-)Rigid H1-Antagonists and Including a Known Interaction Site on the Receptor

“…The model shows that the interacting basic nitrogen occupies largely different positions within the antagonist binding site. For clarity, the fits are presented separately in Figure The Histamine H,-Receptor Antagonist Binding Site cyproheptadine (1) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1.36 phenindamine (2) 0 (S)-4-Me-diphenhydramine (8) 0,16 0.14 5.50 6.17 " All results are with respect to cyproheptadine. b Distance between the ring centroids of the cis-rings, ' Distance between the ring centroids of the trans-rings, J Angle between the cis-rings. ''…”

“…For several decades, almost all compounds with known histamine Hi-blocking activity shared a common ter Laak et al Histamine Hi-antagonists used for the development of the Hi-antagonist binding site model: cyproheptadine (1), phenindamine (2), trans-triprolidine (3), epinastine (4), mequitazine (5), IBF28145 (6), mianserine (7), and (R)-4-methyldiphenhydramine (8).…”

Development of a Receptor-Interaction Model for Serotonin 5-HT2 Receptor Antagonists. Predicting Selectivity with Respect to Dopamine D2 Receptors

“…On the basis of conformational analysis of 8a, using the semiempirical quantum mechanical method MNDO and structural comparisons with other antihistaminergics, it was suggested that the active conformation at the histamine Hi receptor is a high-energy conformation with the piperidine ring in a boat conformation. 34 The energy of the suggested active conformation was determined to be 2.7 kcal/mol higher than the energy of the global minimumenergy conformation corresponding to conformer A. Danitracen (9) has high affinity for 5-HT2 receptors and potent anticholinergic properties.35 9 was minimized by MM2(91) with the hydroxy group in a pseudoequatorial position and the piperidine ring in the two possible chair conformations with the N-methyl group in equatorial positions. As for the cyproheptadine derivatives 8a and 8b, the two conformers have essentially the same conformational energies.…”

Prescribed drugs containing nitrogen heterocycles: an overview

“…381 As a matter of fact, loratadine, cetirizine and astemizole are secondgeneration antihistamines that have substituted rstgeneration antihistamines for example diphenhydramine and ketotifen. [382][383][384][385][386][387][388] Loratadine 362 can be produced via various routes. It can be effectively synthesized, based on the formerly reported approaches, 389 starting from the 8-chloro-5,6-dihydro-11H-benzo [5,6]cyclohepta [1,2-b]pyridin-11-one ketone 356, which upon treatment with an appropriate Grignard reagent 355 afforded the respective tertiary carbinol that was subsequently dehydrated in acidic media giving the 8-chlorol-1piperidiylidene derivative 359.…”