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9-[4-Hydroxy-3-(hydroxymethyl)butyl]guanine (3HM-HBG), (RS)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine ([±]2HM-HBG), and cis-9-(4-hydroxy-2-butenyl)guanine (2EN-HBG), new acyclic guanosine analogs structurally related to buciclovir (BCV [(R)-9-(3,4-dihydroxybutyl)guanine]), were evaluated in parallel with buciclovir as anti-herpes simplex virus (HSV) agents. In cell cultures, replication of different strains of HSV type 1 (HSV-1) and HSV-2 was inhibited at nontoxic drug concentrations. The concentrations giving 50% inhibition of plaque formation were, however, dependent on virus strain and cell type. In most cell types, the order of activity against HSV-1 strains was 3HM-HBG > (±)2HM-HBG > BCV > 2EN-HBG, whereas the drugs showed an approximately equivalent activity against HSV-2 strains in different cells. The cytotoxic effects of the drugs were also cell type dependent, the order of activity being BCV > 3HM-HBG = (±)2HM-HBG > 2EN-HBG. At growth-inhibitory concentrations, the guanosine analogs BCV, 3HM-HBG, and (±)2HM-HBG showed clastogenic effects in human lymphocytes, mainly because of the induction of chromatid breaks. When evaluated for their anti-HSV effects in systemic HSV-1 infections in mice, the order of activity was BCV = 3HM-HBG > (±)2HM-HBG > 2EN-HBG, and in mice infected systemically with HSV-2, only BCV and 3HM-HBG showed efficacy. The differences between efficacy in vitro and in vivo could be explained in part by differences in kinetics of the drugs in mouse plasma, as the more efficacious drugs, BCV and 3HM-HBG, showed lower clearances and longer half-lives than the less efficacious ones, (±)2HM-HBG and 2EN-HBG. When used topically against a cutaneous HSV-1 infection in guinea pigs, 3HM-HBG showed an effect equivalent to that of BCV, whereas (±)2HM-HBG and 2EN-HBG were inactive. Mechanistically, the guanosine analogs were characterized by a high affinity for the viral thymidine kinase and a low affinity for a cellular thymidine kinase and by their inhibition of viral DNA synthesis in infected cells.Some acyclic guanosine analogs were recently reported to be selective antiherpesvirus agents (for reviews, see references 9, 25, 28). We reported that the acyclic guanosine analogs 9-(4-hydroxybutyl)guanine (HBG) and (R)-9(3,4-dihydroxybutyl)guanine (buciclovir [BCV]) were inhibitors of herpes simplex virus (HSV) replication in cell cultures (10,21,22). In addition, BCV showed efficacy in some experimental HSV infections in mice and guinea pigs (10,22). The specificities of HBG and BCV are determined by their selective phosphorylation to monophosphates by viral thymidine kinases and a preferential inhibition of viral DNA synthesis by their triphosphates (21)(22)(23)33). For example, in HSV type 1 (HSV-1)-infected cells, BCV is rapidly phosphorylated to BCV triphosphate, a specific inhibitor of the viral DNA polymerases (33).A number of new acyclic guanosine analogs, structurally related to BCV and HBG, were synthesized, and a few of these were inhibitors of HSV-1 replication in cell culture (19). The ...

Three acyclic guanosine analogs with similar structures, the (R) and (S) forms of 9-(3,4-dihydroxybutyl)guanine and 9-(4-hydroxybutyl)guanine, were compared for antiherpes activity in vivo and in vitro. The three guanosine analogs were viral thymidine kinase-dependent inhibitors of virus multiplication. In ceil cultures, (S)-9-(3,4-dihydroxybutyl)guanine was the least active of these three drugs against a variety of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) strains. This was also the case for a certain HSV-1 or HSV-2 strain in different cell lines, In cell cultures, (R)-9-(3,4-dihydroxybutyl)guanine and 9-(4-hydroxybutyl)guanine had similar antiherpes activities. However, in vivo in cutaneous HSV-1 infections in guinea pigs treated topically and in systemic HSV-2 infections in mice treated orally or intraperitoneally, only (R)-9-(3,4-dihydroxybutyl)guanine had a therapeutic effect. The extremely short half-life in plasma and the high clearance of 9-(4-hydroxybutyl)guanine as compared with those of (R)-9-(3,4-dihydroxybutyl)guanine probably made 9-(4-hydroxybutyl)guanine inefficacious when given intraperitoneally or orally to mice infected with herpesvirus. On the other hand, no kinetic differences between (R)-9-(3,4-dihydroxybutyl)guanine and 9-(4-hydroxybutyl)guanine were observed in penetration through guinea pig skin ex vivo, and no preferential metabolism of 9-(4-hydroxybutyl)guanine in skin was noted. We deduced that high thyntidine levels in guinea pig skin preferentially antagonize the antiviral effect of 9-(4-hydroxybutyl)guanine in cutaneous HSV-1 infections.The acyclic guanosine analogs 9-(4-hydroxybutyl)guanine (HBG) and 9-(3,4-dihydroxybutyl)guanine [(RS)-DHBG] (Fig. 1) are inhibitors of herpes simplex virus (HSV) replication in cell cultures (11,13,14). Their specificities are largely determined by selective phosphorylation to monophosphates by viral thymidine kinases. The compounds are poor substrates for cellular thymidine kinases. The antiviral effects of HBG and (RS)-DHBG coincide with a preferential inhibition of viral DNA synthesis in infected cells (11,13 (11)(12)(13)(14). The difference in phosphorylation rate is 7-fold for H4SV type 1 (HSV-1) thymidine kinase and 2.5-fold for HSV type 2 (HSV-2) thymidine kinase. Nevertheless, in inhibiting HSV-1 or HSV-2 replication in infected Vero cells, HBG and (RS)-DHBG have similar activities.In this study, we present a more extensive comparison of the antiviral effects in vitro and in vivo of HBG and the two enantiomeric forms of DHBG, (R)-DHBG and (S)-DHBG (Fig. 1)

Fifteen healthy male volunteers received single doses of 100 mg immediate release remoxipride (IR), 150 mg controlled release remoxipride (CR), 50 mg chlorpromazine (CPZ), 2 mg lorazepam (LZ), and placebo in a randomised, five-period cross-over study. Both saccadic (SEM) and smooth pursuit eye movements (SPEM) as well as a battery of psychomotor performance tests were assessed at 1.5-h intervals over 9 h following drug administration. The areas under the response-time curves and the maximum effect during the study period were analysed by analysis of variance. The most consistent impairments were produced by LZ. The neuroleptics caused impairments to SEM, and tended to impair critical flicker fusion, continuous attention and both paced and unpaced versions of the digit-symbol substitution test as well as subjective measures of sedation. Only LZ impaired SPEM. Neither paced nor unpaced psychomotor tests distinguished between neuroleptics and benzodiazepines. The low therapeutic doses of IR and CR produced similar impairments to a sub-therapeutic dose of CPZ. Selectivity of pharmacological action does not appear to predict selectivity of effect on psychomotor function.

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