Novel Carbamates as Potent Histamine H 3 Receptor Antagonists with High in Vitro and Oral in Vivo Activity †,⊥ Holger Stark, | Katja Purand, | Xavier Ligneau, ‡ Agne `s Rouleau, § Jean-Michel Arrang, § Monique Garbarg, § Jean-Charles Schwartz, § and Walter Schunack* ,| Institut fu ¨ r Pharmazie, Freie Universita ¨ t Berlin, Ko ¨ nigin-Luise-Strasse 2+4, D-14195 Berlin, Germany, Laboratoire Bioprojet, 3 Avenue Pasteur, F-92430 Marnes-la-Coquette, France, and Unite ´ de Neurobiologie et Pharmacologie, Centre Paul Broca de l’INSERM, 2ter rue d’Ale ´ sia, F-75014 Paris, France Received October 16, 1995 X The known histamine H 3 receptor antagonists burimamide, thioperamide, clobenpropit, and a related homohistamine thioamide derivative were taken as templates in search for new leads. Novel histamine H 3 receptor antagonists structurally described as carbamate derivatives of 3-(1H-imidazol-4-yl)propanol were prepared in high yields by treatment of the alcohol with corresponding isocyanates or carbamoyl chlorides and investigated for their H 3 receptor antagonist activity. Different chain lengths and various substituents possessing different electronic and steric parameters were introduced and structure-activity relationships estab- lished. In different functional tests, the new antagonists showed high H 3 receptor antagonist potencies in vitro (-log K i values of 6.4-8.4) at synaptosomes of rat cerebral cortex and low activities at histamine H 1 and H 2 receptor subtypes. They were also screened for their central in vivo activity in mice after peroral administration. The most promising compounds (2, 16, 19) showed ED 50 values of about 1-2 mg/kg and thus are potential drugs for the therapy of H 3 receptor dependent diseases. Some of the novel carbamate derivatives are H 3 receptor selective compounds with high in vitro and in vivo activity. Introduction While the function of histamine as an autacoid has been known for a long time, the neurotransmitter function of this biogenic amine has been established especially during the last decade. 1 With the identifica- tion of the third histamine receptor subtype acting as a presynaptically located autoreceptor on histaminergic nerve endings, the neurotransmitter function of hista- mine was manifested. 2,3 Activation of histamine H 3 receptors leads to both an inhibition of histamine synthesis from L-histidine and an inhibition of hista- mine release from vesicles in histaminergic neurons. Histamine H 3 receptor antagonists increase histamine synthesis and release by inhibiting a presently unknown negative feedback mechanism. 4 Although H 3 receptors were identified in peripheral tissues in different species, the highest density of this receptor is generally identi- fied in the central nervous system (CNS) where it was detected first on rat cerebral cortex 2 and afterwards also in the human brain. 5 Histamine H 3 receptors are not only autoreceptors; they also act as heteroreceptors. A modulating effect on the release of several neurotrans- mitters was an indication for the general regulatory role of H 3 receptors in neurotransmission, e.g., the influence of the release of noradrenaline, 6 serotonin, 7 acetylcho- line, 8 dopamine, 9 and neuropeptides from nonadrenergic noncholinergic (NANC) nerves. 10 On account of the highest density of H 3 receptors in the CNS and the importance of these neurotransmitters, the therapeutic use of H 3 receptor ligands seems to be especially useful for different CNS disorders. By increasing the brain histamine level, H 3 receptor antagonists have a stimu- lating effect on different cerebral functions and therefore influence different psychic diseases or disorders, e.g., epilepsy, 11 stress, 12 food intake, 13 sleeping, 14 vertigo, 15 or Morbus Alzheimer. At present the indications for the therapeutic use are not totally clear. New pharmacological tools are highly required to clarify these pharmacological problems and clinical usefulness. With regard to further drug development, the new ligands should be highly potent and selective for histamine H 3 receptors and avoid any predictable toxicity. A number of potent and selective H 3 receptor antago- nists possess sulfur-containing functionalities, e.g., the thiourea derivatives burimamide 2 and thioperamide, 16 the isothiourea derivative clobenpropit, 17 and FUB 126, 18 a thioamide derivative of homohistamine (Chart 1). Thioperamide is active in nanomolar and cloben- propit in subnanomolar concentration in vitro. Both compounds are also active in vivo, whereby clobenpropit is clearly less effective than thioperamide (cf. Table 1). None of these compounds have ever been reported to † Presented in part: XXIIIrd Annual Meeting of the European Histamine Research Society (Abstract p 118), Budapest, May 18-21, 1994, 2nd European Congress of the Federation of Pharmaceutical Sciences (Abstracts FC22 and P85), Berlin, September 29-October 1, 1994, and PCT Int. Appl. 21 ⊥ Dedicated to Prof. Dr. Dres. h. c. Herbert Oelschla ¨ ger, Jena, Germany, on the occasion of his 75th birthday. * Author to whom correspondence should be addressed. | Freie Universita ¨ t Berlin. ‡ Laboratoire Bioprojet. § Centre Paul Broca de l′INSERM. X Abstract published in Advance ACS Abstracts, February 1, 1996. Chart 1. Sulfur-Containing Histamine H 3 Receptor Antagonists 1157 J. Med. Chem. 1996, 39, 1157-1163 0022-2623/96/1839-1157$12.00/0 © 1996 American Chemical Society